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Kelch proteins: emerging roles in skeletal muscle development and diseases

Kelch proteins: emerging roles in skeletal muscle development and diseases Our understanding of genes that cause skeletal muscle disease has increased tremendously over the past three decades. Advances in approaches to genetics and genomics have aided in the identification of new pathogenic mechanisms in rare genetic disorders and have opened up new avenues for therapeutic interventions by identification of new molecular pathways in muscle disease. Recent studies have identified mutations of several Kelch proteins in skeletal muscle disorders. The Kelch superfamily is one of the largest evolutionary conserved gene families. The 66 known family members all possess a Kelch-repeat containing domain and are implicated in diverse biological functions. In skeletal muscle development, several Kelch family members regulate the processes of proliferation and/or differentiation resulting in normal functioning of mature muscles. Importantly, many Kelch proteins function as substrate-specific adaptors for Cullin E3 ubiquitin ligase (Cul3), a core component of the ubiquitin-proteasome system to regulate the protein turnover. This review discusses the emerging roles of Kelch proteins in skeletal muscle function and disease. Keywords: Kelch, BTB, BACK, Nemaline myopathy, Dystrophy, Congenital myopathy, Cul3, Ubiquitination, Proteasome, Skeletal muscle, Proliferation, Differentiation Review cores, nemaline rods, central nuclei, various intracytoplas- Skeletal muscle development is a highly coordinated mic inclusions, or fiber type disproportion, and so on process that involves the myogenesis and differentiation [10,11]. Collectively, these diseases are both phenotypically of primary myoblasts, and their integrated growth and and clinically heterogeneous. Gene discovery in muscle development into a mature functional organ [1-4]. Con- diseases is currently skyrocketing due to the use of next- sequently, mutations of a large number of proteins asso- generation sequencing approaches [12-19]. The discovery ciated with development and/or maintenance of skeletal of new genes is not only crucial for improving diagnostics muscle result in disease states. Over the past three for these highly heterogeneous muscular disorders, but decades, tremendous progress has been made in eluci- also is critical for identifying new molecular pathways dating the genetic basis of muscle diseases. Primary that may serve as potential therapeutic targets. Recent inherited diseases of skeletal muscle include the muscu- gene discoveries have identified mutations in Kelch pro- lar dystrophies and the non-dystrophic congenital myop- tein genes as the cause of muscle diseases in humans athies [5-8]. Muscular dystrophies are characterized by [14,20-22]. Kelch proteins belong to the Kelch superfamily myofiber degeneration with repeated rounds of regener- that consists of a large number of structurally and func- ation that ultimately lead to an end-stage process typi- tionally diverse proteins characterized by the presence of a fied by fibrosis and replacement by adipose tissue [9,10]. Kelch-repeat domain [23,24]. Kelch family members are In contrast, non-dystrophic myopathies exhibit little nec- involved in a number of cellular and molecular processes rotic or regenerative changes, but muscle biopsies often such as cell migration, cytoskeletal arrangement, regula- display characteristic structural changes such as central tion of cell morphology, protein degradation, and gene ex- pression [25-31]. This review summarizes our emerging understanding of the various roles of Kelch proteins in * Correspondence: beggs@enders.tch.harvard.edu skeletal muscle development and disease (Tables 1 and 2). Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA © 2014 Gupta and Beggs; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 2 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 Table 1 Kelch family proteins in skeletal muscle development Gene Protein Function Expression KLHL19 KLHL19, KEAP1 Oxidative stress and insulin signaling in muscle cells [32] Ubiquitous [33] KLHL31 KLHL31 Skeletal and cardiac muscle myogenesis [29,34] Skeletal muscle, heart (low levels in brain, kidney, and liver) [29] KLHL39 KLHL39, IVNS1ABP Protection against drug-induced cardiomyopathy [35] Ubiquitous [36] KLHL40 (KBTBD5) KLHL40 Skeletal muscle differentiation [14,37] Skeletal muscle [14] KLHL41 (KBTBD10,KRP1) KLHL41, Sarcosin Skeletal muscle differentiation and myofibril assembly [22,38,39] Skeletal muscle, lungs [22] MKLN1 MKLN1, Muskelin Muscle cell adhesion and extracellular communication [40] Skeletal muscle, brain [40,41] KLHDC1 KLHDC1 Muscle cell migration and differentiation [42,43] Skeletal muscle [42] KLHDC2 KLHDC2 Muscle cell migration and differentiation [42,43] Skeletal muscle [42] Kelch protein superfamily (KLHDC10), Lish and CTLH (MKLN1) domains, in The Kelch superfamily includes 66 genes, of which 63 addition to traditional Kelch repeats. are protein-coding whereas three are non-coding genes. A phylogenetic analysis of human Kelch family pro- The Kelch protein family is primarily classified into teins shows that most members within each subfamily KLHL, KBTBD, and KLHDC subfamilies that differ in largely cluster together with the KLHDC subfamily, that the types and numbers of their protein domains (http:// lacks BTB and BACK domains, apparently having di- www.genenames.org/) (Figure 1A). A prototypic member verged first (Figure 2A). However, several members are of the Kelch family contains an N-terminal BTB/POZ clustered with other subfamilies suggesting that some domain, a BACK domain, and two to eight C-terminal gain or loss of BTB or BACK domains may have occa- Kelch motifs [61]. KLHL subfamily members contain all sionally occurred at later stages of evolution. Kelch pro- of these domains whereas the KBTBD subfamily mem- teins bind to specific substrates through their Kelch bers typically lack the BACK domain [24]. KLHDC domains. An amino acid alignment of only the Kelch subfamily members do not contain either BTB or BACK repeat regions shows that proteins involved in similar domains (Figure 1B and 1C). However, some KLHDC disease processes are clustered together (for example, subfamily members do contain alternative domains, KLHL40, KLHL41, and KBTBD13, all of which cause such as the transmembrane (KLHDC7A), Glycine rich nemaline myopathy) (Figure 2B). This suggests that Table 2 Kelch family proteins in human diseases Gene Function Expression Neuromuscular diseases KLHL1 Spinocerebellar ataxia type 8 [44] Brain, prostate, small intestine, colon [44] KLHL9 Distal myopathy [20] Ubiquitous [20] KLHL16 (GAN) Giant axonal neuropathy [45] Brain, skeletal muscle, heart, kidney, liver [46] KLHL40 (KBTBD5) Severe nemaline myopathy with fetal akinesia [14,37] Skeletal muscle [14] KLHL41 (KBTBD10) Nemaline myopathy [22,38,39] Skeletal muscle, lungs [22] KBTBD13 Nemaline myopathy with cores [21] Skeletal muscle, lungs, heart [21] Cancer KLHL6 Chronic lymphocytic leukemia [47] Lymphocytes (unknown in other tissues) [48] KLHL19 (KEAP1) Pulmonary papillary adenocarcinoma [49] Ubiquitous [50] KLHL20 Prostate cancer progression [51] Ubiquitous [52] KLHL37 (ENC1) Brain tumors [53] Brain (unknown in other tissues) [54] KLHDC8B Hodgkin’s lymphoma [55] Unknown Other Inherited Diseases KLHL3 Pseudohypoalsosteronism type II [56] Cerebellum, kidney, spinal cord, heart, lung, placenta, testis, arota [56] KLHL7 Autosomal dominant retinitis pigmentosa [57] Ubiquitous [57] KLHL10 Oligozoospermia [58,59] Testis [60] Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 3 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 AB Kelch Family (63) KBTBD KLHDC KLHL (9) (12) (42) Kelch Repeats BTB BACK K K KK K KLHL K K KK K BTB KBTBD K K KK K KLHDC OR K K KK K Figure 1 The Kelch Superfamily. (A) The Kelch family consists of 63 proteins that are subclassified in to KLHL, KBTBD and KLHDC subfamilies. (B) Structure of Kelch domain of rat KLHL41 (PDB code 2WOZ) comprising six repeats that form the complete Kelch domain. The structure was generated using PyMOL (www.pymol.org). (C) Prototype members of different subfamilies showing different domain organization. KLHL proteins have an N-terminal BTB/POZ, a BACK and C-terminal Kelch repeats. KBTBD proteins contain an N-terminal BTB domain and Kelch repeats. The BACK domain is normally absent in KBTBD proteins. KLHDC proteins lack both BTB/POZ and BACK domains and contain either Kelch repeats alone or with other domains such as transmembrane (for example, KLHDC7A), Glycine rich (for example, KLHDC10), or Lish and CTLH domains (for example, MKLN1). Kelch domains with high sequence homology may be the most important known interactive role of the BTB regulating similar biological processes through interac- domain is to act as an adaptor between E3 ubiquitin li- tions with shared or related binding partners. Under gases and Kelch domains in order to form active ubi- this model, functional differences between these related quitination complexes [66-68]. In non-Kelch families of Kelch family members will likely derive from variation in proteins, BTB protein-regulated interactions typically in- other domains of the proteins. volve recruitment of co-activators or repressors to tran- scription complexes. In addition, these interacting proteins BTB/POZ domain are also involved in cytoskeletal arrangement and ion con- The BTB/POZ domain derives its name from the ductance [69-72]. Drosophila Bric-a-brac, Tramtrac, and Broad complex due to sequence homology [62,63]. As the DNA poxvirus in BACK domain which this domain was first identified also showed some The BACK domains found in KLHL subfamily members similarity to zinc finger proteins, this domain was concur- are the most conserved domain of the Kelch family and are rently named the POZ (Poxvirus and Zinc finger) domain. present between the N-terminal BTB and C-terminal Kelch BTB domains are mainly involved in facilitating self- domains. BACK domains contain an N-terminal conserved oligomerization or mediating protein-protein interactions Asn-Cys-Leu-Gly-Ile motif and a Val-Arg-[Leu/Met/Phe]- with other proteins [64,65]. Despite the similar secondary Pro-Leu-Leu sequence, two arginines, four glutamic acids, structures and shared organization of BTB proteins, their and several hydrophobic positions causing them to be primary sequences are not well conserved. This sequence hydrophobic in nature [61]. The true role of the BACK do- variability between BTB proteins contributes to differen- main is not known, but it is predicted to participate in tial protein-protein interactions and results in different BTB-E3 ubiquitin ligase complex formation [61]. Evidence functional roles. BTB domains are also present in other for the functional significance of BACK domains comes non Kelch-repeat containing proteins. The major differ- from recent studies where missense mutations in this do- ence lies in the protein interactors of BTB domains in main in KLHL40 and KLHL41 are pathogenic in human Kelch versus non-Kelch proteins. In the Kelch family, patients affected with nemaline myopathy [14,22]. Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 4 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 KLHL1 (NP_065917.1) * KLHL2 (NP_009177.3) AB KLHL5 (NP_057074.3) KLHL3 (NP_059111.2) # KLHL4 (NP_061990.2) KLHL19 (NP_987096.1) ** KLHL8 (NP_065854.3) KLHL10 (AAS91792.1) # KLHL17 (NP_938073.1) KLHL39 (AAH67739.1) KLHL2 (NP_009177.3) KLHL17 (NP_938073.1) KLHL3 (NP_059111.2) # KLHL20 (NP_055273.2) ** KLHL12 (NP_067646.1) KLHL27 (NP_005888.1) KLHL27 (NP_005888.1) KLHL5 (NP_057074.3) KLHL20 (NP_055273.2) ** KLHL1 (NP_065917.1) * KLHL10(AAS91792.1) # KLHL4 (NP_061990.2) KLHL19 (NP_987096.1) ** KLHL12 (NP_067646.1) KLHL39 (AAH67739.1) KLHL8 (NP_065854.3) KLHL28 (NP_060128.2|) KLHL18 (NP_079286.2) KLHL18 (NP_079286.2) KLHL28 (NP_060128.2) KLHL7 (NP_001026880.2) # KLHL16 (NP_071324.1) * KLHL11 (NP_060613.1) KLHL7 (NP_001026880) # KLHL16 (NP_071324.1) * KLHL40 (NP_689606.2) * KLHL23 (AAH10437.2) KLHL41 (NP_006054.2) * KBTBD4 (NP_060565.4) KBTBD13 (NP_001094832.1) * KLHL21 (NP_055666.2|) KLHL33 (NP_001103467.2) KLHL30 (NP_940984.3) KLHDC8A (AAH36076.1) KLHL25 (AAH28100.1) KLHDC8B (NP_775817.1) ** KLHL37 (NP_001243504.1) ** KLHL22 (NP_116164.2) KLHL29 (NP_443152.1) KLHL31 (NP_001003760.2) KLHL38 (AAI27887.1) KLHL24 (NP_060114.2) KLHL35 ( NP_001034637.2) KLHL6 (NP_569713.2) ** KLHL24 (NP_060114.2) KLHL25 (AAH28100.1) KLHL6 (NP_569713.2|) ** KLHL37 (NP_001243504.1 **) KBTBD12 (NP_997218.2) KLHL11 (NP_060613.1) KBTBD3 (AAI17467.1) KLHL30 (NP_940984.3) KLHL40 (NP_689606.2) * KLHL21 (NP_055666.2) KLHL41 (NP_006054.2) * KBTBD4 (NP_060565.4) KLHL38 (AAI27887.1) KBTBD8 (NP_115894.2) KBTBD2 (AAH37887.1) KLHL23 (AAH10437.2) KBTBD6 (AAH00560.1) KLHDC4 (NP_060036.2) KBTBD7 (CAG38589.1) KLHL42 (NP_065833.1) KLHDC7A (NP_689588.2) KBTBD3 (AAI17467.1) KLHDC7B (NP_612442.2) KLHDC7B (NP_612442.2) KBTBD11 (NP_055682.1) KBTBD11 (NP_05568.2) KLHL42 (NP_065833.1) KLHDC7A (NP_689588.2) KBTBD13 (NP_001094832.1) * KBTBD12 (NP_997218.2) KLHL33 (NP_001103467.2) KLHL15 (AAI09060.1) KLHL32 (NP_443136.2) KLHL34 (NP_695002.1) KLHL34 (NP_695002.1) KBTBD6 (AAH00560.1) KLHL14 (NP_065856.1) KBTBD7 (CAG38589.1) KLHL31 (NP_001003760.2) KBTBD2 (AAH37887.1) KLHL15 (AAI09060.1) KBTBD8 (NP_115894.2) KLHL22 (NP_116164.2) KLHL14 (NP_065856.1) KLHL26 (NP_060786.1) KLHL26 (NP_060786.1) KLHL36 (NP_079007.2) KLHL32 (NP_443136.2) KLHL13 (NP_277030.2) KLHL36 (NP_079007.2) KLHL9 (NP_061335.1) * KLHL13 (NP_277030.2) KLHDC10 (NP_055812.1) KLHL9 (NP_061335.1) * KLHDC8A (AAH36076.1) MKLN1 (EAL24081.1) KLHDC8B (NP_775817.1) ** KLHDC1 (NP_751943.1) KLHDC3 (AAH09460.1) KLHDC2 (CAG33486.1) MKLN1 (EAL24081.1) KLHDC3 (AAH09460.1) RABEPKP1 (AAH47023.1) RABEPK (AAH47023.1) KLHDC4 (NP_060036.2) KLHDC10 (NP_055812.1) KLHDC9 (AAH66896.1) KLHDC9 (AAH66896.1) KLHDC1 (NP_751943.1) KLHL29 (NP_443152.1) KLHDC2 (CAG33486.1) KLHL35 (NP_001034637.2) 1 1 Figure 2 Phylogenetic analysis showing relationships between human Kelch protein family members. (A) Phylogenetic tree of full-length amino acid sequences of human proteins were aligned. (B) Phylogenetic tree of amino acid sequences of Kelch domains. Phylogenetic trees were constructed by maximum-likelihood method using BLOSUM matrix in MEGA 6.06. Reference sequences used for alignments are indicated at right of each protein name. Blue highlighting indicates KBTBD subfamily members; green indicates KLHDC subfamily members. *, proteins involved in neuromuscular diseases; **, family members implicated in cancer; #, proteins whose defects cause other inherited diseases (Table 2). Scale bars indicate relative distances and represent the degree of differences between the sequences. Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 5 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 Kelch domain IV neurofilaments. Therefore, a mis-regulation of Aurora Kelch motifs range from 44 to 56 amino acids in length B Kinase function in KLHL9 deficiency is postulated to and are usually arranged in a series of five to seven repeats affect normal skeletal muscle function [76]. in most of the family members [23]. The signature motifs in each Kelch repeat are a series of four hydrophobic KBTBD13 amino acids followed by glycine doublet, a conserved tyro- KBTBD13 is a member of the KBTBD subfamily of sine, and a conserved tryptophan. Each Kelch repeat folds Kelch proteins that contains a BTB domain and Kelch into four twisted antiparallel β-strands connected by repeats but lacks a BACK domain. KBTBD13 mutations intrablade loops to form a single blade of a β-propeller result in an autosomal dominant form of nemaline my- (Figure 1B). A C-terminal strand closure mechanism links opathy associated with cores in affected patients [21]. the first and last blades to complete the propeller. Kelch Clinically, patients with KBTBD13 mutations exhibit β-propellers primarily function as scaffolds for protein- poor exercise tolerance, gait abnormality, and progres- protein interactions. Despite the shared tertiary structure, sive weakness of the neck and proximal limb muscles. there is little primary sequence identity between one Kelch The peculiar clinical feature specific to KBTBD13 pa- repeat and another, suggesting a wide diversity of interact- tients that is not seen in other forms of congenital my- ing partners across the Kelch superfamily. In nemaline my- opathies is a characteristic slowness of movement, where opathy, all pathogenic KBTBD13 mutations identified to patients are unable to run and correct themselves from date in human patients were found in the Kelch repeats falling over. Moreover, skeletal muscles of patients with [21]. Similarly, mutations in Kelch repeats of both KLHL40 KBTBD13 mutations exhibit cores that lack oxidative or KLHL41 also result in nemaline myopathy [14,22]. enzymatic activity and show predominance as well as hypertrophy of type 1 (slow) myofibers [21]. The Kelch proteins in skeletal muscle diseases localization of KBTBD13 in myofibers is not clear. KLHL9 Localization studies have shown that KBTBD13 does The first Kelch protein defect reported in a primary skel- not co-localize with α-actin (thin filament protein) or etal muscle disease was of KLHL9, resulting in an early α-actinin (a Z-line marker), suggesting a different onset autosomal dominant form of distal myopathy [20]. localization and mechanism of action than previously Distal myopathies are a heterogeneous group of muscle known proteins in nemaline myopathy, which primarily diseases characterized by progressive muscular atrophy localize to thin filaments [21]. All known pathogenic and weakness, beginning in distal (hence the name) and mutations in KBTBD13 are localized in the Kelch re- progressing to proximal limb muscles [73]. By linkage peats of the protein and are predicted to damage the analysis and subsequence candidate sequencing, Cirak β-propeller blades. KBTBD13 forms a complex with et al. identified a p.Leu95Phe missense change in the Cul3 ubiquitin ligase through its N-terminal BTB do- N-Terminal BTB domain of KLHL9 in several affected main and this interaction is required for the formation members of a single large German family with a domin- of a functional Cul3 ubiquitin ligase complex, suggesting ant form of distal myopathy [20]. Leucine is conserved that the pathogenic mechanism in KBTBD13-related at this position in other vertebrates, and molecular mod- nemaline myopathy may involve dysregulation of cellular eling predicted that the change to phenylalanine would protein ubiquitination [66]. affect BTB domain conformation and likely disrupt the protein-protein interactions with Cul3 ubiquitin ligase. Cell culture studies subsequently showed that wild-type KLHL40 KLHL9 interacted with Cul3 ubiquitin ligase whereas KLHL40 mutations have been recently identified as a the p.Leu95Phe mutation disrupted the KLHL9-Cul3 cause of nemaline myopathy in a severe form of the interaction [20,74]. The Kelch family members act as disease [14]. KLHL40 belongs to the KLHL subfamily substrate-recognizing adaptors of the Cul3 ubiquitina- of Kelch proteins that contain an N-terminal BTB do- tion complex, which targets specific substrates for ubi- main, a BACK domain, and five Kelch repeats on the quitination and subsequent degradation by proteasomal C-terminal end. Recessive mutations in KLHL40 are as- pathways. While experimental evidence for KLHL9 as a sociated with fetal akinesia or hypokinesia during the regulator of ubiquitination in skeletal muscles is still prenatal period, respiratory failure, and swallowing diffi- lacking, one potential substrate for KLHL9 action is pos- culty at birth, as well as contractures, fractures, and tulated to be Aurora B kinase [20]. Previous studies have dysmorphic features that in many cases are associated shown that KLHL9 targets this kinase during mitotic with early death. A significant number of patients with progression and cytokinesis [75]. Aurora B kinase is a KLHL40 mutations (approximately 17%) also exhibit regulator of assembly and disassembly of type III inter- ophthalmoparesis that is usually not present in other mediate filaments including vimentin, desmin, and type genetic subtypes of nemaline myopathy. Moreover, Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 6 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 fractures are also a relatively frequent presentation in in addition to Z-line thickening as seen in human nema- KLHL40 patients that is not commonly seen in other line myopathy patients. forms of nemaline and other congenital myopathies. Previous studies have shown that KLHL41 interacts Mutations of KLHL40 have been found in exons encod- with Cul3 ubiquitin ligase to form functional ubiquitina- ing all domains of the protein with a majority of the mu- tion complexes with proteins targeted for degradation tations seen in the Kelch repeats, including a founder [78]. The identification of protein substrates targeted by mutation (p.Glu528Lys) present in Japanese, Turkish, the KLHL41-Cul3 ubiquitin complex is not known. and Kurdish populations. Both truncating as well as mis- KLHL41 interacts with nebulin [79] and co-localizes sense mutations are seen in KLHL40. Knockdown of with actin [80], mutations of which cause approximately KLHL40 orthologues in zebrafish results in sarcomeric 65% to 70% of all known mutations in patients affected abnormalities and impaired locomotion similar to hu- with nemaline myopathy [81]. The high degree of se- man patients, providing further evidence that KLHL40 is quence similarity between Kelch repeats of KBTBD13, the disease-causing gene in nemaline myopathy [14]. KLHL40, and KLHL41 suggests that they may share Murine Klhl40 protein is localized at triads along with identical or closely related binding partners whose dys- the sarcoplasmic reticulum (SR) marker Ryr1 [22]. regulation leads to nemaline myopathy through a com- KLHL40 interacts with CUL3 ubiquitin ligase via the mon final pathway and implicates a critical role for N-terminal BTB domain and forms a protein complex, BTB-Kelch family members in the maintenance of sarco- the functional significance of which remains to be unrav- meric integrity in skeletal muscle. eled [68]. Recent work has also shown that Klhl40 promoter is a direct target of myoD and is crucial for Kelch proteins in skeletal muscle development muscle cell differentiation [22,37]. Members of the Kelch family are known to be involved in multiple biological processes such as migration, cyto- KLHL41 skeletal arrangement, regulation of cell morphology, KLHL41 is the most recent member of the Kelch family myofibril assembly, protein degradation, and gene ex- to be implicated in muscle disease. Unlike KLHL9 and pression [25,27,45,80,82,83]. Several Kelch proteins asso- KBTBD13 mutations that cause a dominant form of the ciate with the actin cytoskeleton via the β-propeller disease, mutations in KLHL41, like KLHL40, result in module, and these associations are important for func- an autosomal recessive form of nemaline myopathy. tional roles of these proteins [84,85]. Other Kelch proteins Genetic analysis of five unrelated families has shown affect the organization of cytoskeletal, plasma membrane, that KLHL41 mutations appear to follow a genotype- or organelle structures but do not bind directly to or phenotype correlation. Mutations that led to truncated co-localize with actin. proteins resulted in a severe form of the disease with In skeletal muscle, many Kelch proteins are known to fetal akinesia, a lack of antigravity movement, arthrogry- regulate the proliferation as well as differentiation of posis, and dislocation of the hip and knees. These pa- muscle cells. KLHL41 is highly expressed in myoblasts tients died within the first few months of life due to during early muscle differentiation [86]. Knockdown as respiratory insufficiency. Missense changes resulted in a well as overexpression of KLHL41 in C2C12 cells inhib- mild or intermediate form of the disease with impaired ited myoblast differentiation, suggesting a role in cell motor functions and survival into late childhood and/or cycle exit and the promotion of differentiation [38]. early adulthood. KLHL41 localizes in the perinuclear Knockdown of KLHL41 in cultured cardiomyocytes area and over (but not within) I bands, in association affected lateral fusion of myofibrils resulting in thin with the terminal cisternae and longitudinal vesicles of myofibrils [39]. In developing chicken and zebrafish the SR membranes present in the I-band area at the embryos, KLHL31 is specifically expressed in early heart triadic regions. As most of the previously known NM and in developing myoblasts shortly after their commit- proteins are components of sarcomeric thin filaments, ment to this fate, signifying an important role during the unique localization of KLHL41, as well as non- skeletal muscle and cardiac myogenesis [29]. The ex- sarcomeric localization of KLHL40 in association with pression of KLHL31 is initiated just after MyoD in devel- the triads, suggests the involvement of new pathophysio- oping skeletal muscles and this expression persisted in logical mechanisms for nemaline myopathy [77]. Knock- later stages of development implying the possible in- down of KLHL41 in zebrafish resulted in skeletal muscle volvement of KLHL31 in the early phases of myogenic myopathy with disorganized and thinner myofibers as commitment and during later muscle differentiation well as reduced motor function in comparison to wild- [34]. KLHL31 acts as a transcriptional repressor in the type zebrafish. Interestingly, morphant fish also exhib- MAPK/JNK signaling pathway in mouse cardiomyocytes. ited numerous electron dense structures in skeletal In skeletal muscle cells, overexpression of KLHDC2 ren- muscle, reminiscent of small or nascent nemaline bodies, dered these cells unable to respond to chemoattractants Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 7 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 and led to augmented stress fiber formation and cell dependent E3 ubiquitination ligase complex during protein adherence [26]. Additionally, myoblasts overexpressing ubiquitination [93,105,106]. KLHDC2 failed to differentiate into mature myotubes. Ubiquitination is a multistep process in which an E1 KLHDC2 also regulates transcription processes by ubiquitination activating enzyme transfers ubiquitin to inducing expression of the leucine zipper transcription an E2 ubiquitin-conjugating enzyme. The final step of factor (LZIP) in muscle cells. KLHDC1 is a paralogue of this process is the ligation of ubiquitin to the substrate, KLHDC2 and shares 50% similarity with KLHDC2. Simi- catalyzed by an E3 ubiquitin protein ligase [107-109]. As lar to KLHDC2, the highest expression of KLHDC1 is the stability of a large number of proteins is controlled observed in skeletal muscles [42]. However, the func- by the ubiquitin system, it is crucial to determine how tional roles of KLHDC1 remain unknown. Muskelin the cell achieves sufficient diversity among E3s so that (MKLN1, a KLHDC subfamily member) was identified each one selectively recognizes only one or a few sub- in an expression cloning screen for molecules that pro- strates in the sea of cellular proteins present at any time. moted cell adhesion to the extracellular matrix compo- Several hundreds of such E3 ligases are described, nent thrombospondin 1. Overexpression or antisense some of which are clearly specific to skeletal muscles depletion of muskelin in mouse skeletal myoblasts corre- [110,111]. One subgroup of E3 ligases are the ubiqui- lates with altered organization of fascin microspike- tously expressed cullins that do not bind to their sub- based adhesive contacts and a redistribution of focal strates directly, but rely on an array of adaptor proteins. contact in TSP-1 adherent cells, yet has modest effects There are seven cullin genes known in mammals on actin organization in cells adherent on fibronectin (CUL1-CUL3, CUL4a, CUL4b, CUL5, and CUL7), but [40]. These results suggest that muskelin functions at only CUL3 interacts with the BTB-Kelch proteins [112]. a node point in the integration of cell responses to Thus, BTB-domain proteins serve as the substrate spe- complex extracellular matrix. As most of muskelin is cific adaptors of CUL3-based E3 ubiquitin ligases [113]. cytoplasmic, its effects on matrix contacts are thought to The crucial requirement of CUL3 function is evident be mediated indirectly. The requirement of Kelch pro- from Cul3 null mice that exhibit embryonic lethality. teins in cell morphology comes from yeast-based studies In particular, Cul3 null homozygous mice exhibit abnor- where mutations in Kelch proteins resulted in cell fusion mal cycling of cells in extraembryonic membranes, re- defects [87]. The emerging roles of Kelch proteins in duced size, abnormal gastrulation and trophoblast cells, metabolic pathways come from a recent study where absence of an amnion, and death by embryonic day 7.5 Keap1 (Klhl19) knockout mice exhibited a significant re- [114]. In humans, dominant CUL3 mutations are associ- duction in insulin signaling pathway gene expression in ated with pseudohypoaldosteronism type II, a genetic skeletal muscles [32,88,89]. Keap1 also regulates redox sig- disorder causing hypertension, hyperkalemia, and meta- naling, as increased oxidative stress thought to be associ- bolic acidosis [92]. Even though CUL3 is ubiquitously ated with its dysregulation is observed in sedentary elderly expressed, the functional specificity of CUL3 in different people [89]. Nd1-L (KLHL39)is an actin binding protein spatial and developmental contexts is exhibited through expressed in high levels in heart that protects against protein-protein interaction with different Kelch proteins. doxorubicin-induced cardiomyopathy in mice [35]. This may in part be regulated by tissue specific expres- sion, and substrate specificity of the different Kelch Molecular pathways regulated by Kelch proteins protein-binding partners. KLHL40 and KLHL41 are pri- Detailed studies on molecular functions of Kelch pro- marily expressed in skeletal (with low expression in cardiac) teins are still largely lacking except with regard to their muscles. In skeletal muscles, deficiency of these proteins roles as substrate specific adaptors in the ubiquitination and thereby a perturbation of Cul3 ubiquitin complex pathways, thereby regulating diverse cellular processes formation to regulate the protein turnover of specific [21,28,90-94]. Skeletal muscle proteins are especially substrates may lead to skeletal muscle diseases. prone to wear and tear as they are the primary force The regulation of ubiquitination by Kelch proteins in generating mechanism in skeletal muscle. A quality skeletal muscles has been investigated in the context of disease. Kelch proteins such as KLHL9, KBTBD13, control check, by removal of damaged proteins and co- ordinated turnover, is performed by many proteolytic KLHL40, and KLHL41 that cause skeletal muscle disorders, systems in skeletal muscles: the caspase and calpain sys- each form protein complexes with CUL3 [20,66,68,78]. The functional significance of these interactions has been tems of partially muscle-specific proteases; the ubiquitin proteasome system (UPS) which degrades polyubiquiti- shown by several studies, as Cul3-KLHL41 and Cul3- nated proteins via the 26S proteasome; and the autophaghy KBTBD13 complexes are able to perform in vitro ubiquiti- nation in the presence of other members of the functional pathway which removes proteins by inclusion in autophagic/ lysosomal vesicles [95-104]. Kelch proteins function by ubiquitination complex [66,78]. Moreover, in distal myop- acting as substrate specific adaptors for the Cullin3- athy, the interaction of mutant KLHL9 with Cul3 is highly Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 8 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 reduced in comparison to wild-type KLHL9, which may in ubiquitination has non-degradative roles such as modula- turn affect the ubiquitination of cellular proteins [20]. tion of protein activity, interaction, and sub-cellular Identifying the protein interactors of each of these Kelch localization of proteins [118,119], so it may be that some proteins in skeletal muscle will provide further insight into of these Kelch proteins actually promote the stability of disease mechanisms. A study of the skeletal muscle inter- their binding partners. Future studies will help us to better actome showed that KLHL41 interacts with TCAP, ENO3, understand these processes in the context of skeletal and SGCG, three proteins encoded by genes mutated in muscle development and diseases. limb-girdle muscular dystrophy type 2G, metabolic myop- athy, and limb-girdle muscular dystrophy type 2C, respect- Kelch proteins in other human diseases ively [79]. This points toward the potential regulatory A number of Kelch proteins play important roles in a roles of Kelch proteins and/or ubiquitination pathways in variety of human diseases, including cancer and neuro- other muscle diseases as well [79,115-117]. KLHL41 also logical disorders [55,120-122] (Table 2). Mutations of interacts with nebulin, a known causative gene of nema- KLHL6, KLHL19, KLHL20, and KLHL37 are associated line myopathy, by protein-protein interactions and is with various forms of cancers [47,49,51,53]. Whole ex- co-localized with actin at the tips of pseudopodia in fibro- ome sequencing in a rare genetic disorder, pseudohy- blasts. These data suggest that KLHL41 and other disease- poalsosteronism type II, involving hypertension, causing Kelch proteins KLHL40, KBTBD13, and KLHL9 hyperkalemia, and metabolic acidosis, recently identi- may contribute to disease pathogenesis by regulating the fied mutations in the KLHL3 gene [56,92]. KLHL3 mu- protein turnover of nebulin, actin, and other important tations are either recessive or dominant in nature. The skeletal muscle proteins that are required for normal recessive mutations are distributed throughout the functioning of skeletal muscle (Figure 3). In the absence encoded protein, whereas dominant mutations were of Kelch proteins, disturbance of this protein turnover localized in the cullin binding sites, likely impairing the process and subsequent overabundance of damaged sarco- formation of active Cul3 complexes. Linkage analysis meric proteins may result in disease states in affected and mutation screening in 502 retinopathy probands muscles (Figure 3). In addition to protein degradation, identified KLHL7 as a cause of autosomal dominant Ub Ub Ub Ub Ub A S2 S1 Ub Ub Ub Ub Ub Ub Ub Ub Ub S3 E2 E2 N8 N8 Rbx1 Rbx1 KLHL41 KLHL41 Cul3 Cul3 Normal Protein Active Cul3 E3 Ligase complex Skeletal Muscle Degradation (Cul3-KLHL41-E2 Ligase) B S3 S1 S2 Ss1 S3 S2 Ub E2 KLHL9 KLHL40 N8 S3 Rbx1 KLHL41 S3 KBTBD13 Diseased Accumulation of Skeletal Muscle undesired proteins Inactive Cul3 E3 Ligase Figure 3 Kelch proteins act as a substrate specific adaptors for E3-ubiquitinin protein complex. (A) Cullin3 complex is Nedd8 (N8) modified and recruits E2-bound ubiquitin through RING-finger protein Rbx1. The assembly of a functional ubiquitination complex requires the binding of Cul3-E2 complex to substrate specific Kelch adaptor proteins. Cul3 directly binds to N-terminal BTB domain of Kelch protein and this E3-ubiquitination complex interacts with substrates (for example, S1, S2, S3) by C-terminal Kelch-repeat containing domains of Kelch proteins, causing ubiquitination of the target proteins and subsequent degradation (or stabilization and so on) by the proteasome system. This results in normal protein turnover of proteins required for normal functioning of muscle resulting in healthy skeletal muscles. (B) The deficiency of Kelch proteins (such as disease causing KLHL9, KLHL40, KLHL41, and KBTBD13) prevents the assembly of functional Cullin3 ubiquitination complex thereby perturbing the protein turnover process. In the model shown here, this results in accumulation of abnormal proteins (for example, S1, S2, S3) leading to unavailability of normal proteins in skeletal muscle leading to a diseased state. Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 9 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 retinitis pigmentosa [57]. Interestingly, the missense related neuromuscular diseases. Dr. Beggs has been associated with the discovery of several new genes associated with congenital muscle diseases as mutations localized in the BACK domain of the KLHL7 well as developing gene and protein based therapies for X-linked myotubular protein were predicted to affect the ubiquitination myopathy. complexes [57]. KLHL10 is specifically expressed in Vandana A Gupta, PhD is an Instructor in Pediatrics at Harvard Medical School and Associate Research Staff in the Division of Genetics and testis and mutations of this gene lead to oligozoosper- Genomics at Boston Children’s Hospital. Dr. Gupta has identified several mia and male infertility. Missense changes in KLHL10 new genes in congenital muscle diseases using zebrafish and human impair homodimerization that is required for normal studies. Dr. Gupta has been awarded many fellowships and conference awards and is currently supported by a K01 AR062601 from the National protein function, resulting in functional deficiency in Institute of Arthritis and Musculoskeletal and Skin Diseases of National patients [58]. Spinocerebellar ataxia type 8 (SCA8) is a Institutes of Health and Charles H. Hood Child Health Grant Foundation. dominantly inherited disorder caused by large CTG re- peat expansions in the untranslated antisense RNA of Acknowledgements VAG is supported by K01 AR062601 from the National Institute of Arthritis the KLHL1 gene [123]. While the molecular disease and Musculoskeletal and Skin Diseases of National Institutes of Health and mechanism is still unclear, reduction of KLHL1 in mice a Charles H. Hood Foundation Child Health Research Grant. This work is leads to the degeneration of Purkinje cell function, sug- supported by the Muscular Dystrophy Association of USA (MDA201302), National Institutes of Health grant from the National Institute of Arthritis and gesting a significant role in the pathophysiology of Musculoskeletal and Skin Diseases R01 AR044345; the AUism Charitable SCA8 [124]. Giant axonal neuropathy (GAN) is a rare Foundation, and A Foundation Building Strength (to AHB). autosomal recessive progressive neurodegenerative dis- Received: 26 March 2014 Accepted: 6 May 2014 order involving the peripheral and central nervous sys- Published: 1 June 2014 tems. A number of mutations in gigaxonin (GAN), a BTB- Kelch protein, have been identified as resulting in a gener- References alized disorganization of cytoskeletal intermediate filaments 1. Jansen KM, Pavlath GK: Molecular control of mammalian myoblast fusion. Methods Mol Biol 2008, 475:115–133. [45,125]. This cytoskeletal disorganization is attributed 2. 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Ohkoshi A, Suzuki T, Ono M, Kobayashi T, Yamamoto M: Roles of • Research which is freely available for redistribution Keap1-Nrf2 system in upper aerodigestive tract carcinogenesis. Cancer Prev Res (Phila) 2013, 6:149–159. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Skeletal Muscle Springer Journals

Kelch proteins: emerging roles in skeletal muscle development and diseases

Skeletal Muscle , Volume 4 (1) – Jun 1, 2014

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Copyright © 2014 by Gupta and Beggs; licensee BioMed Central Ltd.
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Life Sciences; Cell Biology; Developmental Biology; Biochemistry, general; Systems Biology; Biotechnology
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24959344
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Abstract

Our understanding of genes that cause skeletal muscle disease has increased tremendously over the past three decades. Advances in approaches to genetics and genomics have aided in the identification of new pathogenic mechanisms in rare genetic disorders and have opened up new avenues for therapeutic interventions by identification of new molecular pathways in muscle disease. Recent studies have identified mutations of several Kelch proteins in skeletal muscle disorders. The Kelch superfamily is one of the largest evolutionary conserved gene families. The 66 known family members all possess a Kelch-repeat containing domain and are implicated in diverse biological functions. In skeletal muscle development, several Kelch family members regulate the processes of proliferation and/or differentiation resulting in normal functioning of mature muscles. Importantly, many Kelch proteins function as substrate-specific adaptors for Cullin E3 ubiquitin ligase (Cul3), a core component of the ubiquitin-proteasome system to regulate the protein turnover. This review discusses the emerging roles of Kelch proteins in skeletal muscle function and disease. Keywords: Kelch, BTB, BACK, Nemaline myopathy, Dystrophy, Congenital myopathy, Cul3, Ubiquitination, Proteasome, Skeletal muscle, Proliferation, Differentiation Review cores, nemaline rods, central nuclei, various intracytoplas- Skeletal muscle development is a highly coordinated mic inclusions, or fiber type disproportion, and so on process that involves the myogenesis and differentiation [10,11]. Collectively, these diseases are both phenotypically of primary myoblasts, and their integrated growth and and clinically heterogeneous. Gene discovery in muscle development into a mature functional organ [1-4]. Con- diseases is currently skyrocketing due to the use of next- sequently, mutations of a large number of proteins asso- generation sequencing approaches [12-19]. The discovery ciated with development and/or maintenance of skeletal of new genes is not only crucial for improving diagnostics muscle result in disease states. Over the past three for these highly heterogeneous muscular disorders, but decades, tremendous progress has been made in eluci- also is critical for identifying new molecular pathways dating the genetic basis of muscle diseases. Primary that may serve as potential therapeutic targets. Recent inherited diseases of skeletal muscle include the muscu- gene discoveries have identified mutations in Kelch pro- lar dystrophies and the non-dystrophic congenital myop- tein genes as the cause of muscle diseases in humans athies [5-8]. Muscular dystrophies are characterized by [14,20-22]. Kelch proteins belong to the Kelch superfamily myofiber degeneration with repeated rounds of regener- that consists of a large number of structurally and func- ation that ultimately lead to an end-stage process typi- tionally diverse proteins characterized by the presence of a fied by fibrosis and replacement by adipose tissue [9,10]. Kelch-repeat domain [23,24]. Kelch family members are In contrast, non-dystrophic myopathies exhibit little nec- involved in a number of cellular and molecular processes rotic or regenerative changes, but muscle biopsies often such as cell migration, cytoskeletal arrangement, regula- display characteristic structural changes such as central tion of cell morphology, protein degradation, and gene ex- pression [25-31]. This review summarizes our emerging understanding of the various roles of Kelch proteins in * Correspondence: beggs@enders.tch.harvard.edu skeletal muscle development and disease (Tables 1 and 2). Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA © 2014 Gupta and Beggs; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 2 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 Table 1 Kelch family proteins in skeletal muscle development Gene Protein Function Expression KLHL19 KLHL19, KEAP1 Oxidative stress and insulin signaling in muscle cells [32] Ubiquitous [33] KLHL31 KLHL31 Skeletal and cardiac muscle myogenesis [29,34] Skeletal muscle, heart (low levels in brain, kidney, and liver) [29] KLHL39 KLHL39, IVNS1ABP Protection against drug-induced cardiomyopathy [35] Ubiquitous [36] KLHL40 (KBTBD5) KLHL40 Skeletal muscle differentiation [14,37] Skeletal muscle [14] KLHL41 (KBTBD10,KRP1) KLHL41, Sarcosin Skeletal muscle differentiation and myofibril assembly [22,38,39] Skeletal muscle, lungs [22] MKLN1 MKLN1, Muskelin Muscle cell adhesion and extracellular communication [40] Skeletal muscle, brain [40,41] KLHDC1 KLHDC1 Muscle cell migration and differentiation [42,43] Skeletal muscle [42] KLHDC2 KLHDC2 Muscle cell migration and differentiation [42,43] Skeletal muscle [42] Kelch protein superfamily (KLHDC10), Lish and CTLH (MKLN1) domains, in The Kelch superfamily includes 66 genes, of which 63 addition to traditional Kelch repeats. are protein-coding whereas three are non-coding genes. A phylogenetic analysis of human Kelch family pro- The Kelch protein family is primarily classified into teins shows that most members within each subfamily KLHL, KBTBD, and KLHDC subfamilies that differ in largely cluster together with the KLHDC subfamily, that the types and numbers of their protein domains (http:// lacks BTB and BACK domains, apparently having di- www.genenames.org/) (Figure 1A). A prototypic member verged first (Figure 2A). However, several members are of the Kelch family contains an N-terminal BTB/POZ clustered with other subfamilies suggesting that some domain, a BACK domain, and two to eight C-terminal gain or loss of BTB or BACK domains may have occa- Kelch motifs [61]. KLHL subfamily members contain all sionally occurred at later stages of evolution. Kelch pro- of these domains whereas the KBTBD subfamily mem- teins bind to specific substrates through their Kelch bers typically lack the BACK domain [24]. KLHDC domains. An amino acid alignment of only the Kelch subfamily members do not contain either BTB or BACK repeat regions shows that proteins involved in similar domains (Figure 1B and 1C). However, some KLHDC disease processes are clustered together (for example, subfamily members do contain alternative domains, KLHL40, KLHL41, and KBTBD13, all of which cause such as the transmembrane (KLHDC7A), Glycine rich nemaline myopathy) (Figure 2B). This suggests that Table 2 Kelch family proteins in human diseases Gene Function Expression Neuromuscular diseases KLHL1 Spinocerebellar ataxia type 8 [44] Brain, prostate, small intestine, colon [44] KLHL9 Distal myopathy [20] Ubiquitous [20] KLHL16 (GAN) Giant axonal neuropathy [45] Brain, skeletal muscle, heart, kidney, liver [46] KLHL40 (KBTBD5) Severe nemaline myopathy with fetal akinesia [14,37] Skeletal muscle [14] KLHL41 (KBTBD10) Nemaline myopathy [22,38,39] Skeletal muscle, lungs [22] KBTBD13 Nemaline myopathy with cores [21] Skeletal muscle, lungs, heart [21] Cancer KLHL6 Chronic lymphocytic leukemia [47] Lymphocytes (unknown in other tissues) [48] KLHL19 (KEAP1) Pulmonary papillary adenocarcinoma [49] Ubiquitous [50] KLHL20 Prostate cancer progression [51] Ubiquitous [52] KLHL37 (ENC1) Brain tumors [53] Brain (unknown in other tissues) [54] KLHDC8B Hodgkin’s lymphoma [55] Unknown Other Inherited Diseases KLHL3 Pseudohypoalsosteronism type II [56] Cerebellum, kidney, spinal cord, heart, lung, placenta, testis, arota [56] KLHL7 Autosomal dominant retinitis pigmentosa [57] Ubiquitous [57] KLHL10 Oligozoospermia [58,59] Testis [60] Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 3 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 AB Kelch Family (63) KBTBD KLHDC KLHL (9) (12) (42) Kelch Repeats BTB BACK K K KK K KLHL K K KK K BTB KBTBD K K KK K KLHDC OR K K KK K Figure 1 The Kelch Superfamily. (A) The Kelch family consists of 63 proteins that are subclassified in to KLHL, KBTBD and KLHDC subfamilies. (B) Structure of Kelch domain of rat KLHL41 (PDB code 2WOZ) comprising six repeats that form the complete Kelch domain. The structure was generated using PyMOL (www.pymol.org). (C) Prototype members of different subfamilies showing different domain organization. KLHL proteins have an N-terminal BTB/POZ, a BACK and C-terminal Kelch repeats. KBTBD proteins contain an N-terminal BTB domain and Kelch repeats. The BACK domain is normally absent in KBTBD proteins. KLHDC proteins lack both BTB/POZ and BACK domains and contain either Kelch repeats alone or with other domains such as transmembrane (for example, KLHDC7A), Glycine rich (for example, KLHDC10), or Lish and CTLH domains (for example, MKLN1). Kelch domains with high sequence homology may be the most important known interactive role of the BTB regulating similar biological processes through interac- domain is to act as an adaptor between E3 ubiquitin li- tions with shared or related binding partners. Under gases and Kelch domains in order to form active ubi- this model, functional differences between these related quitination complexes [66-68]. In non-Kelch families of Kelch family members will likely derive from variation in proteins, BTB protein-regulated interactions typically in- other domains of the proteins. volve recruitment of co-activators or repressors to tran- scription complexes. In addition, these interacting proteins BTB/POZ domain are also involved in cytoskeletal arrangement and ion con- The BTB/POZ domain derives its name from the ductance [69-72]. Drosophila Bric-a-brac, Tramtrac, and Broad complex due to sequence homology [62,63]. As the DNA poxvirus in BACK domain which this domain was first identified also showed some The BACK domains found in KLHL subfamily members similarity to zinc finger proteins, this domain was concur- are the most conserved domain of the Kelch family and are rently named the POZ (Poxvirus and Zinc finger) domain. present between the N-terminal BTB and C-terminal Kelch BTB domains are mainly involved in facilitating self- domains. BACK domains contain an N-terminal conserved oligomerization or mediating protein-protein interactions Asn-Cys-Leu-Gly-Ile motif and a Val-Arg-[Leu/Met/Phe]- with other proteins [64,65]. Despite the similar secondary Pro-Leu-Leu sequence, two arginines, four glutamic acids, structures and shared organization of BTB proteins, their and several hydrophobic positions causing them to be primary sequences are not well conserved. This sequence hydrophobic in nature [61]. The true role of the BACK do- variability between BTB proteins contributes to differen- main is not known, but it is predicted to participate in tial protein-protein interactions and results in different BTB-E3 ubiquitin ligase complex formation [61]. Evidence functional roles. BTB domains are also present in other for the functional significance of BACK domains comes non Kelch-repeat containing proteins. The major differ- from recent studies where missense mutations in this do- ence lies in the protein interactors of BTB domains in main in KLHL40 and KLHL41 are pathogenic in human Kelch versus non-Kelch proteins. In the Kelch family, patients affected with nemaline myopathy [14,22]. Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 4 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 KLHL1 (NP_065917.1) * KLHL2 (NP_009177.3) AB KLHL5 (NP_057074.3) KLHL3 (NP_059111.2) # KLHL4 (NP_061990.2) KLHL19 (NP_987096.1) ** KLHL8 (NP_065854.3) KLHL10 (AAS91792.1) # KLHL17 (NP_938073.1) KLHL39 (AAH67739.1) KLHL2 (NP_009177.3) KLHL17 (NP_938073.1) KLHL3 (NP_059111.2) # KLHL20 (NP_055273.2) ** KLHL12 (NP_067646.1) KLHL27 (NP_005888.1) KLHL27 (NP_005888.1) KLHL5 (NP_057074.3) KLHL20 (NP_055273.2) ** KLHL1 (NP_065917.1) * KLHL10(AAS91792.1) # KLHL4 (NP_061990.2) KLHL19 (NP_987096.1) ** KLHL12 (NP_067646.1) KLHL39 (AAH67739.1) KLHL8 (NP_065854.3) KLHL28 (NP_060128.2|) KLHL18 (NP_079286.2) KLHL18 (NP_079286.2) KLHL28 (NP_060128.2) KLHL7 (NP_001026880.2) # KLHL16 (NP_071324.1) * KLHL11 (NP_060613.1) KLHL7 (NP_001026880) # KLHL16 (NP_071324.1) * KLHL40 (NP_689606.2) * KLHL23 (AAH10437.2) KLHL41 (NP_006054.2) * KBTBD4 (NP_060565.4) KBTBD13 (NP_001094832.1) * KLHL21 (NP_055666.2|) KLHL33 (NP_001103467.2) KLHL30 (NP_940984.3) KLHDC8A (AAH36076.1) KLHL25 (AAH28100.1) KLHDC8B (NP_775817.1) ** KLHL37 (NP_001243504.1) ** KLHL22 (NP_116164.2) KLHL29 (NP_443152.1) KLHL31 (NP_001003760.2) KLHL38 (AAI27887.1) KLHL24 (NP_060114.2) KLHL35 ( NP_001034637.2) KLHL6 (NP_569713.2) ** KLHL24 (NP_060114.2) KLHL25 (AAH28100.1) KLHL6 (NP_569713.2|) ** KLHL37 (NP_001243504.1 **) KBTBD12 (NP_997218.2) KLHL11 (NP_060613.1) KBTBD3 (AAI17467.1) KLHL30 (NP_940984.3) KLHL40 (NP_689606.2) * KLHL21 (NP_055666.2) KLHL41 (NP_006054.2) * KBTBD4 (NP_060565.4) KLHL38 (AAI27887.1) KBTBD8 (NP_115894.2) KBTBD2 (AAH37887.1) KLHL23 (AAH10437.2) KBTBD6 (AAH00560.1) KLHDC4 (NP_060036.2) KBTBD7 (CAG38589.1) KLHL42 (NP_065833.1) KLHDC7A (NP_689588.2) KBTBD3 (AAI17467.1) KLHDC7B (NP_612442.2) KLHDC7B (NP_612442.2) KBTBD11 (NP_055682.1) KBTBD11 (NP_05568.2) KLHL42 (NP_065833.1) KLHDC7A (NP_689588.2) KBTBD13 (NP_001094832.1) * KBTBD12 (NP_997218.2) KLHL33 (NP_001103467.2) KLHL15 (AAI09060.1) KLHL32 (NP_443136.2) KLHL34 (NP_695002.1) KLHL34 (NP_695002.1) KBTBD6 (AAH00560.1) KLHL14 (NP_065856.1) KBTBD7 (CAG38589.1) KLHL31 (NP_001003760.2) KBTBD2 (AAH37887.1) KLHL15 (AAI09060.1) KBTBD8 (NP_115894.2) KLHL22 (NP_116164.2) KLHL14 (NP_065856.1) KLHL26 (NP_060786.1) KLHL26 (NP_060786.1) KLHL36 (NP_079007.2) KLHL32 (NP_443136.2) KLHL13 (NP_277030.2) KLHL36 (NP_079007.2) KLHL9 (NP_061335.1) * KLHL13 (NP_277030.2) KLHDC10 (NP_055812.1) KLHL9 (NP_061335.1) * KLHDC8A (AAH36076.1) MKLN1 (EAL24081.1) KLHDC8B (NP_775817.1) ** KLHDC1 (NP_751943.1) KLHDC3 (AAH09460.1) KLHDC2 (CAG33486.1) MKLN1 (EAL24081.1) KLHDC3 (AAH09460.1) RABEPKP1 (AAH47023.1) RABEPK (AAH47023.1) KLHDC4 (NP_060036.2) KLHDC10 (NP_055812.1) KLHDC9 (AAH66896.1) KLHDC9 (AAH66896.1) KLHDC1 (NP_751943.1) KLHL29 (NP_443152.1) KLHDC2 (CAG33486.1) KLHL35 (NP_001034637.2) 1 1 Figure 2 Phylogenetic analysis showing relationships between human Kelch protein family members. (A) Phylogenetic tree of full-length amino acid sequences of human proteins were aligned. (B) Phylogenetic tree of amino acid sequences of Kelch domains. Phylogenetic trees were constructed by maximum-likelihood method using BLOSUM matrix in MEGA 6.06. Reference sequences used for alignments are indicated at right of each protein name. Blue highlighting indicates KBTBD subfamily members; green indicates KLHDC subfamily members. *, proteins involved in neuromuscular diseases; **, family members implicated in cancer; #, proteins whose defects cause other inherited diseases (Table 2). Scale bars indicate relative distances and represent the degree of differences between the sequences. Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 5 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 Kelch domain IV neurofilaments. Therefore, a mis-regulation of Aurora Kelch motifs range from 44 to 56 amino acids in length B Kinase function in KLHL9 deficiency is postulated to and are usually arranged in a series of five to seven repeats affect normal skeletal muscle function [76]. in most of the family members [23]. The signature motifs in each Kelch repeat are a series of four hydrophobic KBTBD13 amino acids followed by glycine doublet, a conserved tyro- KBTBD13 is a member of the KBTBD subfamily of sine, and a conserved tryptophan. Each Kelch repeat folds Kelch proteins that contains a BTB domain and Kelch into four twisted antiparallel β-strands connected by repeats but lacks a BACK domain. KBTBD13 mutations intrablade loops to form a single blade of a β-propeller result in an autosomal dominant form of nemaline my- (Figure 1B). A C-terminal strand closure mechanism links opathy associated with cores in affected patients [21]. the first and last blades to complete the propeller. Kelch Clinically, patients with KBTBD13 mutations exhibit β-propellers primarily function as scaffolds for protein- poor exercise tolerance, gait abnormality, and progres- protein interactions. Despite the shared tertiary structure, sive weakness of the neck and proximal limb muscles. there is little primary sequence identity between one Kelch The peculiar clinical feature specific to KBTBD13 pa- repeat and another, suggesting a wide diversity of interact- tients that is not seen in other forms of congenital my- ing partners across the Kelch superfamily. In nemaline my- opathies is a characteristic slowness of movement, where opathy, all pathogenic KBTBD13 mutations identified to patients are unable to run and correct themselves from date in human patients were found in the Kelch repeats falling over. Moreover, skeletal muscles of patients with [21]. Similarly, mutations in Kelch repeats of both KLHL40 KBTBD13 mutations exhibit cores that lack oxidative or KLHL41 also result in nemaline myopathy [14,22]. enzymatic activity and show predominance as well as hypertrophy of type 1 (slow) myofibers [21]. The Kelch proteins in skeletal muscle diseases localization of KBTBD13 in myofibers is not clear. KLHL9 Localization studies have shown that KBTBD13 does The first Kelch protein defect reported in a primary skel- not co-localize with α-actin (thin filament protein) or etal muscle disease was of KLHL9, resulting in an early α-actinin (a Z-line marker), suggesting a different onset autosomal dominant form of distal myopathy [20]. localization and mechanism of action than previously Distal myopathies are a heterogeneous group of muscle known proteins in nemaline myopathy, which primarily diseases characterized by progressive muscular atrophy localize to thin filaments [21]. All known pathogenic and weakness, beginning in distal (hence the name) and mutations in KBTBD13 are localized in the Kelch re- progressing to proximal limb muscles [73]. By linkage peats of the protein and are predicted to damage the analysis and subsequence candidate sequencing, Cirak β-propeller blades. KBTBD13 forms a complex with et al. identified a p.Leu95Phe missense change in the Cul3 ubiquitin ligase through its N-terminal BTB do- N-Terminal BTB domain of KLHL9 in several affected main and this interaction is required for the formation members of a single large German family with a domin- of a functional Cul3 ubiquitin ligase complex, suggesting ant form of distal myopathy [20]. Leucine is conserved that the pathogenic mechanism in KBTBD13-related at this position in other vertebrates, and molecular mod- nemaline myopathy may involve dysregulation of cellular eling predicted that the change to phenylalanine would protein ubiquitination [66]. affect BTB domain conformation and likely disrupt the protein-protein interactions with Cul3 ubiquitin ligase. Cell culture studies subsequently showed that wild-type KLHL40 KLHL9 interacted with Cul3 ubiquitin ligase whereas KLHL40 mutations have been recently identified as a the p.Leu95Phe mutation disrupted the KLHL9-Cul3 cause of nemaline myopathy in a severe form of the interaction [20,74]. The Kelch family members act as disease [14]. KLHL40 belongs to the KLHL subfamily substrate-recognizing adaptors of the Cul3 ubiquitina- of Kelch proteins that contain an N-terminal BTB do- tion complex, which targets specific substrates for ubi- main, a BACK domain, and five Kelch repeats on the quitination and subsequent degradation by proteasomal C-terminal end. Recessive mutations in KLHL40 are as- pathways. While experimental evidence for KLHL9 as a sociated with fetal akinesia or hypokinesia during the regulator of ubiquitination in skeletal muscles is still prenatal period, respiratory failure, and swallowing diffi- lacking, one potential substrate for KLHL9 action is pos- culty at birth, as well as contractures, fractures, and tulated to be Aurora B kinase [20]. Previous studies have dysmorphic features that in many cases are associated shown that KLHL9 targets this kinase during mitotic with early death. A significant number of patients with progression and cytokinesis [75]. Aurora B kinase is a KLHL40 mutations (approximately 17%) also exhibit regulator of assembly and disassembly of type III inter- ophthalmoparesis that is usually not present in other mediate filaments including vimentin, desmin, and type genetic subtypes of nemaline myopathy. Moreover, Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 6 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 fractures are also a relatively frequent presentation in in addition to Z-line thickening as seen in human nema- KLHL40 patients that is not commonly seen in other line myopathy patients. forms of nemaline and other congenital myopathies. Previous studies have shown that KLHL41 interacts Mutations of KLHL40 have been found in exons encod- with Cul3 ubiquitin ligase to form functional ubiquitina- ing all domains of the protein with a majority of the mu- tion complexes with proteins targeted for degradation tations seen in the Kelch repeats, including a founder [78]. The identification of protein substrates targeted by mutation (p.Glu528Lys) present in Japanese, Turkish, the KLHL41-Cul3 ubiquitin complex is not known. and Kurdish populations. Both truncating as well as mis- KLHL41 interacts with nebulin [79] and co-localizes sense mutations are seen in KLHL40. Knockdown of with actin [80], mutations of which cause approximately KLHL40 orthologues in zebrafish results in sarcomeric 65% to 70% of all known mutations in patients affected abnormalities and impaired locomotion similar to hu- with nemaline myopathy [81]. The high degree of se- man patients, providing further evidence that KLHL40 is quence similarity between Kelch repeats of KBTBD13, the disease-causing gene in nemaline myopathy [14]. KLHL40, and KLHL41 suggests that they may share Murine Klhl40 protein is localized at triads along with identical or closely related binding partners whose dys- the sarcoplasmic reticulum (SR) marker Ryr1 [22]. regulation leads to nemaline myopathy through a com- KLHL40 interacts with CUL3 ubiquitin ligase via the mon final pathway and implicates a critical role for N-terminal BTB domain and forms a protein complex, BTB-Kelch family members in the maintenance of sarco- the functional significance of which remains to be unrav- meric integrity in skeletal muscle. eled [68]. Recent work has also shown that Klhl40 promoter is a direct target of myoD and is crucial for Kelch proteins in skeletal muscle development muscle cell differentiation [22,37]. Members of the Kelch family are known to be involved in multiple biological processes such as migration, cyto- KLHL41 skeletal arrangement, regulation of cell morphology, KLHL41 is the most recent member of the Kelch family myofibril assembly, protein degradation, and gene ex- to be implicated in muscle disease. Unlike KLHL9 and pression [25,27,45,80,82,83]. Several Kelch proteins asso- KBTBD13 mutations that cause a dominant form of the ciate with the actin cytoskeleton via the β-propeller disease, mutations in KLHL41, like KLHL40, result in module, and these associations are important for func- an autosomal recessive form of nemaline myopathy. tional roles of these proteins [84,85]. Other Kelch proteins Genetic analysis of five unrelated families has shown affect the organization of cytoskeletal, plasma membrane, that KLHL41 mutations appear to follow a genotype- or organelle structures but do not bind directly to or phenotype correlation. Mutations that led to truncated co-localize with actin. proteins resulted in a severe form of the disease with In skeletal muscle, many Kelch proteins are known to fetal akinesia, a lack of antigravity movement, arthrogry- regulate the proliferation as well as differentiation of posis, and dislocation of the hip and knees. These pa- muscle cells. KLHL41 is highly expressed in myoblasts tients died within the first few months of life due to during early muscle differentiation [86]. Knockdown as respiratory insufficiency. Missense changes resulted in a well as overexpression of KLHL41 in C2C12 cells inhib- mild or intermediate form of the disease with impaired ited myoblast differentiation, suggesting a role in cell motor functions and survival into late childhood and/or cycle exit and the promotion of differentiation [38]. early adulthood. KLHL41 localizes in the perinuclear Knockdown of KLHL41 in cultured cardiomyocytes area and over (but not within) I bands, in association affected lateral fusion of myofibrils resulting in thin with the terminal cisternae and longitudinal vesicles of myofibrils [39]. In developing chicken and zebrafish the SR membranes present in the I-band area at the embryos, KLHL31 is specifically expressed in early heart triadic regions. As most of the previously known NM and in developing myoblasts shortly after their commit- proteins are components of sarcomeric thin filaments, ment to this fate, signifying an important role during the unique localization of KLHL41, as well as non- skeletal muscle and cardiac myogenesis [29]. The ex- sarcomeric localization of KLHL40 in association with pression of KLHL31 is initiated just after MyoD in devel- the triads, suggests the involvement of new pathophysio- oping skeletal muscles and this expression persisted in logical mechanisms for nemaline myopathy [77]. Knock- later stages of development implying the possible in- down of KLHL41 in zebrafish resulted in skeletal muscle volvement of KLHL31 in the early phases of myogenic myopathy with disorganized and thinner myofibers as commitment and during later muscle differentiation well as reduced motor function in comparison to wild- [34]. KLHL31 acts as a transcriptional repressor in the type zebrafish. Interestingly, morphant fish also exhib- MAPK/JNK signaling pathway in mouse cardiomyocytes. ited numerous electron dense structures in skeletal In skeletal muscle cells, overexpression of KLHDC2 ren- muscle, reminiscent of small or nascent nemaline bodies, dered these cells unable to respond to chemoattractants Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 7 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 and led to augmented stress fiber formation and cell dependent E3 ubiquitination ligase complex during protein adherence [26]. Additionally, myoblasts overexpressing ubiquitination [93,105,106]. KLHDC2 failed to differentiate into mature myotubes. Ubiquitination is a multistep process in which an E1 KLHDC2 also regulates transcription processes by ubiquitination activating enzyme transfers ubiquitin to inducing expression of the leucine zipper transcription an E2 ubiquitin-conjugating enzyme. The final step of factor (LZIP) in muscle cells. KLHDC1 is a paralogue of this process is the ligation of ubiquitin to the substrate, KLHDC2 and shares 50% similarity with KLHDC2. Simi- catalyzed by an E3 ubiquitin protein ligase [107-109]. As lar to KLHDC2, the highest expression of KLHDC1 is the stability of a large number of proteins is controlled observed in skeletal muscles [42]. However, the func- by the ubiquitin system, it is crucial to determine how tional roles of KLHDC1 remain unknown. Muskelin the cell achieves sufficient diversity among E3s so that (MKLN1, a KLHDC subfamily member) was identified each one selectively recognizes only one or a few sub- in an expression cloning screen for molecules that pro- strates in the sea of cellular proteins present at any time. moted cell adhesion to the extracellular matrix compo- Several hundreds of such E3 ligases are described, nent thrombospondin 1. Overexpression or antisense some of which are clearly specific to skeletal muscles depletion of muskelin in mouse skeletal myoblasts corre- [110,111]. One subgroup of E3 ligases are the ubiqui- lates with altered organization of fascin microspike- tously expressed cullins that do not bind to their sub- based adhesive contacts and a redistribution of focal strates directly, but rely on an array of adaptor proteins. contact in TSP-1 adherent cells, yet has modest effects There are seven cullin genes known in mammals on actin organization in cells adherent on fibronectin (CUL1-CUL3, CUL4a, CUL4b, CUL5, and CUL7), but [40]. These results suggest that muskelin functions at only CUL3 interacts with the BTB-Kelch proteins [112]. a node point in the integration of cell responses to Thus, BTB-domain proteins serve as the substrate spe- complex extracellular matrix. As most of muskelin is cific adaptors of CUL3-based E3 ubiquitin ligases [113]. cytoplasmic, its effects on matrix contacts are thought to The crucial requirement of CUL3 function is evident be mediated indirectly. The requirement of Kelch pro- from Cul3 null mice that exhibit embryonic lethality. teins in cell morphology comes from yeast-based studies In particular, Cul3 null homozygous mice exhibit abnor- where mutations in Kelch proteins resulted in cell fusion mal cycling of cells in extraembryonic membranes, re- defects [87]. The emerging roles of Kelch proteins in duced size, abnormal gastrulation and trophoblast cells, metabolic pathways come from a recent study where absence of an amnion, and death by embryonic day 7.5 Keap1 (Klhl19) knockout mice exhibited a significant re- [114]. In humans, dominant CUL3 mutations are associ- duction in insulin signaling pathway gene expression in ated with pseudohypoaldosteronism type II, a genetic skeletal muscles [32,88,89]. Keap1 also regulates redox sig- disorder causing hypertension, hyperkalemia, and meta- naling, as increased oxidative stress thought to be associ- bolic acidosis [92]. Even though CUL3 is ubiquitously ated with its dysregulation is observed in sedentary elderly expressed, the functional specificity of CUL3 in different people [89]. Nd1-L (KLHL39)is an actin binding protein spatial and developmental contexts is exhibited through expressed in high levels in heart that protects against protein-protein interaction with different Kelch proteins. doxorubicin-induced cardiomyopathy in mice [35]. This may in part be regulated by tissue specific expres- sion, and substrate specificity of the different Kelch Molecular pathways regulated by Kelch proteins protein-binding partners. KLHL40 and KLHL41 are pri- Detailed studies on molecular functions of Kelch pro- marily expressed in skeletal (with low expression in cardiac) teins are still largely lacking except with regard to their muscles. In skeletal muscles, deficiency of these proteins roles as substrate specific adaptors in the ubiquitination and thereby a perturbation of Cul3 ubiquitin complex pathways, thereby regulating diverse cellular processes formation to regulate the protein turnover of specific [21,28,90-94]. Skeletal muscle proteins are especially substrates may lead to skeletal muscle diseases. prone to wear and tear as they are the primary force The regulation of ubiquitination by Kelch proteins in generating mechanism in skeletal muscle. A quality skeletal muscles has been investigated in the context of disease. Kelch proteins such as KLHL9, KBTBD13, control check, by removal of damaged proteins and co- ordinated turnover, is performed by many proteolytic KLHL40, and KLHL41 that cause skeletal muscle disorders, systems in skeletal muscles: the caspase and calpain sys- each form protein complexes with CUL3 [20,66,68,78]. The functional significance of these interactions has been tems of partially muscle-specific proteases; the ubiquitin proteasome system (UPS) which degrades polyubiquiti- shown by several studies, as Cul3-KLHL41 and Cul3- nated proteins via the 26S proteasome; and the autophaghy KBTBD13 complexes are able to perform in vitro ubiquiti- nation in the presence of other members of the functional pathway which removes proteins by inclusion in autophagic/ lysosomal vesicles [95-104]. Kelch proteins function by ubiquitination complex [66,78]. Moreover, in distal myop- acting as substrate specific adaptors for the Cullin3- athy, the interaction of mutant KLHL9 with Cul3 is highly Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 8 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 reduced in comparison to wild-type KLHL9, which may in ubiquitination has non-degradative roles such as modula- turn affect the ubiquitination of cellular proteins [20]. tion of protein activity, interaction, and sub-cellular Identifying the protein interactors of each of these Kelch localization of proteins [118,119], so it may be that some proteins in skeletal muscle will provide further insight into of these Kelch proteins actually promote the stability of disease mechanisms. A study of the skeletal muscle inter- their binding partners. Future studies will help us to better actome showed that KLHL41 interacts with TCAP, ENO3, understand these processes in the context of skeletal and SGCG, three proteins encoded by genes mutated in muscle development and diseases. limb-girdle muscular dystrophy type 2G, metabolic myop- athy, and limb-girdle muscular dystrophy type 2C, respect- Kelch proteins in other human diseases ively [79]. This points toward the potential regulatory A number of Kelch proteins play important roles in a roles of Kelch proteins and/or ubiquitination pathways in variety of human diseases, including cancer and neuro- other muscle diseases as well [79,115-117]. KLHL41 also logical disorders [55,120-122] (Table 2). Mutations of interacts with nebulin, a known causative gene of nema- KLHL6, KLHL19, KLHL20, and KLHL37 are associated line myopathy, by protein-protein interactions and is with various forms of cancers [47,49,51,53]. Whole ex- co-localized with actin at the tips of pseudopodia in fibro- ome sequencing in a rare genetic disorder, pseudohy- blasts. These data suggest that KLHL41 and other disease- poalsosteronism type II, involving hypertension, causing Kelch proteins KLHL40, KBTBD13, and KLHL9 hyperkalemia, and metabolic acidosis, recently identi- may contribute to disease pathogenesis by regulating the fied mutations in the KLHL3 gene [56,92]. KLHL3 mu- protein turnover of nebulin, actin, and other important tations are either recessive or dominant in nature. The skeletal muscle proteins that are required for normal recessive mutations are distributed throughout the functioning of skeletal muscle (Figure 3). In the absence encoded protein, whereas dominant mutations were of Kelch proteins, disturbance of this protein turnover localized in the cullin binding sites, likely impairing the process and subsequent overabundance of damaged sarco- formation of active Cul3 complexes. Linkage analysis meric proteins may result in disease states in affected and mutation screening in 502 retinopathy probands muscles (Figure 3). In addition to protein degradation, identified KLHL7 as a cause of autosomal dominant Ub Ub Ub Ub Ub A S2 S1 Ub Ub Ub Ub Ub Ub Ub Ub Ub S3 E2 E2 N8 N8 Rbx1 Rbx1 KLHL41 KLHL41 Cul3 Cul3 Normal Protein Active Cul3 E3 Ligase complex Skeletal Muscle Degradation (Cul3-KLHL41-E2 Ligase) B S3 S1 S2 Ss1 S3 S2 Ub E2 KLHL9 KLHL40 N8 S3 Rbx1 KLHL41 S3 KBTBD13 Diseased Accumulation of Skeletal Muscle undesired proteins Inactive Cul3 E3 Ligase Figure 3 Kelch proteins act as a substrate specific adaptors for E3-ubiquitinin protein complex. (A) Cullin3 complex is Nedd8 (N8) modified and recruits E2-bound ubiquitin through RING-finger protein Rbx1. The assembly of a functional ubiquitination complex requires the binding of Cul3-E2 complex to substrate specific Kelch adaptor proteins. Cul3 directly binds to N-terminal BTB domain of Kelch protein and this E3-ubiquitination complex interacts with substrates (for example, S1, S2, S3) by C-terminal Kelch-repeat containing domains of Kelch proteins, causing ubiquitination of the target proteins and subsequent degradation (or stabilization and so on) by the proteasome system. This results in normal protein turnover of proteins required for normal functioning of muscle resulting in healthy skeletal muscles. (B) The deficiency of Kelch proteins (such as disease causing KLHL9, KLHL40, KLHL41, and KBTBD13) prevents the assembly of functional Cullin3 ubiquitination complex thereby perturbing the protein turnover process. In the model shown here, this results in accumulation of abnormal proteins (for example, S1, S2, S3) leading to unavailability of normal proteins in skeletal muscle leading to a diseased state. Gupta and Beggs Skeletal Muscle 2014, 4:11 Page 9 of 12 http://www.skeletalmusclejournal.com/content/4/1/11 retinitis pigmentosa [57]. Interestingly, the missense related neuromuscular diseases. Dr. Beggs has been associated with the discovery of several new genes associated with congenital muscle diseases as mutations localized in the BACK domain of the KLHL7 well as developing gene and protein based therapies for X-linked myotubular protein were predicted to affect the ubiquitination myopathy. complexes [57]. KLHL10 is specifically expressed in Vandana A Gupta, PhD is an Instructor in Pediatrics at Harvard Medical School and Associate Research Staff in the Division of Genetics and testis and mutations of this gene lead to oligozoosper- Genomics at Boston Children’s Hospital. Dr. Gupta has identified several mia and male infertility. Missense changes in KLHL10 new genes in congenital muscle diseases using zebrafish and human impair homodimerization that is required for normal studies. Dr. Gupta has been awarded many fellowships and conference awards and is currently supported by a K01 AR062601 from the National protein function, resulting in functional deficiency in Institute of Arthritis and Musculoskeletal and Skin Diseases of National patients [58]. Spinocerebellar ataxia type 8 (SCA8) is a Institutes of Health and Charles H. Hood Child Health Grant Foundation. dominantly inherited disorder caused by large CTG re- peat expansions in the untranslated antisense RNA of Acknowledgements VAG is supported by K01 AR062601 from the National Institute of Arthritis the KLHL1 gene [123]. While the molecular disease and Musculoskeletal and Skin Diseases of National Institutes of Health and mechanism is still unclear, reduction of KLHL1 in mice a Charles H. Hood Foundation Child Health Research Grant. This work is leads to the degeneration of Purkinje cell function, sug- supported by the Muscular Dystrophy Association of USA (MDA201302), National Institutes of Health grant from the National Institute of Arthritis and gesting a significant role in the pathophysiology of Musculoskeletal and Skin Diseases R01 AR044345; the AUism Charitable SCA8 [124]. Giant axonal neuropathy (GAN) is a rare Foundation, and A Foundation Building Strength (to AHB). autosomal recessive progressive neurodegenerative dis- Received: 26 March 2014 Accepted: 6 May 2014 order involving the peripheral and central nervous sys- Published: 1 June 2014 tems. A number of mutations in gigaxonin (GAN), a BTB- Kelch protein, have been identified as resulting in a gener- References alized disorganization of cytoskeletal intermediate filaments 1. Jansen KM, Pavlath GK: Molecular control of mammalian myoblast fusion. Methods Mol Biol 2008, 475:115–133. [45,125]. This cytoskeletal disorganization is attributed 2. 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North KN, Wang CH, Clarke N, Jungbluth H, Vainzof M, Dowling JJ, discovery of these proteins in skeletal muscle diseases Amburgey K, Quijano-Roy S, Beggs AH, Sewry C, Laing NG, Bonnemann CG, and function is very exciting, both in terms of improving International Standard of Care Committee for Congenital Myopathies: diagnostics and opening up new directions of research Approach to the diagnosis of congenital myopathies. Neuromuscul Disord 2014, 24:97–116. on cellular and molecular pathways crucial for skeletal 12. Torella A, Fanin M, Mutarelli M, Peterle E, Del Vecchio BF, Rispoli R, Savarese muscle function. Further studies on ubiquitination and M, Garofalo A, Piluso G, Morandi L, Ricci G, Siciliano G, Angelini C, Nigro V: the identification of Kelch substrates in skeletal muscle Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F. PLoS One 2013, 8:e63536. will help us to develop suitable therapeutics for a wide 13. Stevens E, Carss KJ, Cirak S, Foley AR, Torelli S, Willer T, Tambunan DE, Yau S, range of muscle diseases and related disorders. Brodd L, Sewry CA, Feng L, Haliloglu G, Orhan D, Dobyns WB, Enns GM, Manning M, Krause A, Salih MA, Walsh CA, Hurles M, Campbell KP, Manzini Competing interests MC, UK10K Consortium, Stemple D, Lin YY, Muntoni F: Mutations in The authors declare that they have no competing interests. B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of alpha-dystroglycan. Am J Hum Genet 2013, 92:354–365. Authors’ contribution 14. Ravenscroft G, Miyatake S, Lehtokari VL, Todd EJ, Vornanen P, Yau KS, VAG and AHB wrote the manuscript. Both authors read and approved the Hayashi YK, Miyake N, Tsurusaki Y, Doi H, Saitsu H, Osaka H, Yamashita S, final manuscript. Ohya T, Sakamoto Y, Koshimizu E, Imamura S, Yamashita M, Ogata K, Shiina M, Bryson-Richardson RJ, Vaz R, Ceyhan O, Brownstein CA, Swanson LC, Authors’ information Monnot S, Romero NB, Amthor H, Kresoje N, Sivadorai P, et al: Mutations in Alan H Beggs, PhD is Sir Edwin and Lady Manton Professor of Pediatrics at KLHL40 Are a frequent cause of severe autosomal-recessive nemaline Harvard Medical School and Research Associate in the Division of Genetics myopathy. Am J Hum Genet 2013, 93:6–18. and Genomics at Boston Children’s Hospital where he is also director of The 15. Carss KJ, Stevens E, Foley AR, Cirak S, Riemersma M, Torelli S, Hoischen A, Manton Center for Orphan Disease Research. 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Journal

Skeletal MuscleSpringer Journals

Published: Jun 1, 2014

References