Cellular and Molecular Life Sciences

Brown, Haley A.; DeVeaux, Anna L.; Juliano, Brock R.; Photenhauer, Amanda L.; Boulinguiez, Matthieu; Bornschein, Russell E.; Wawrzak, Zdzislaw; Ruotolo, Brandon T.; Terrapon, Nicolas; Koropatkin, Nicole M.

doi: 10.1007/s00018-023-04812-wpmid: 37500984

Members of the Bacteroidetes phylum in the human colon deploy an extensive number of proteins to capture and degrade polysaccharides. Operons devoted to glycan breakdown and uptake are termed polysaccharide utilization loci or PUL. The starch utilization system (Sus) is one such PUL and was initially described in Bacteroides thetaiotaomicron (Bt). BtSus is highly conserved across many species, except for its extracellular α-amylase, SusG. In this work, we show that the Bacteroides ovatus (Bo) extracellular α-amylase, BoGH13ASus, is distinguished from SusG in its evolutionary origin and its domain architecture and by being the most prevalent form in Bacteroidetes Sus. BoGH13ASus is the founding member of both a novel subfamily in the glycoside hydrolase family 13, GH13_47, and a novel carbohydrate-binding module, CBM98. The BoGH13ASus CBM98–CBM48–GH13_47 architecture differs from the CBM58 embedded within the GH13_36 of SusG. These domains adopt a distinct spatial orientation and invoke a different association with the outer membrane. The BoCBM98 binding site is required for Bo growth on polysaccharides and optimal enzymatic degradation thereof. Finally, the BoGH13ASus structure features bound Ca2+ and Mn2+ ions, the latter of which is novel for an α-amylase. Little is known about the impact of Mn2+ on gut bacterial function, much less on polysaccharide consumption, but Mn2+ addition to Bt expressing BoGH13ASus specifically enhances growth on starch. Further understanding of bacterial starch degradation signatures will enable more tailored prebiotic and pharmaceutical approaches that increase starch flux to the gut.

Li, Kunming; Wei, Xiumei; Li, Kang; Zhang, Qian; Zhang, Jiansong; Wang, Ding; Yang, Jialong

doi: 10.1007/s00018-023-04865-xpmid: 37470873

Recent advances highlight a key role of transient fasting in optimizing immunity of human and mouse. However, it remains unknown whether this strategy is independently acquired by mammals during evolution or instead represents gradually evolved functions common to vertebrates. Using a tilapia model, we report that T cells are the main executors of the response of the immune system to fasting and that dietary restriction bidirectionally modulates T cell immunity. Long-term fasting impaired T cell immunity by inducing intense autophagy, apoptosis, and aberrant inflammation. However, transient dietary restriction triggered moderate autophagy to optimize T cell response by maintaining homeostasis, alleviating inflammation and tissue damage, as well as enhancing T cell activation, proliferation and function. Furthermore, AMPK is the central hub linking fasting and autophagy-controlled T cell immunity in tilapia. Our findings demonstrate that dietary restriction to optimize immunity is an ancient strategy conserved in vertebrate evolution, providing novel perspectives for understanding the adaptive evolution of T cell response.

Galow, Anne-Marie; Brenmoehl, Julia; Hoeflich, Andreas

doi: 10.1007/s00018-023-04894-6pmid: 37541969

The limited endogenous regenerative capacity of the human heart renders cardiovascular diseases a major health threat, thus motivating intense research on in vitro heart cell generation and cell replacement therapies. However, so far, in vitro-generated cardiomyocytes share a rather fetal phenotype, limiting their utility for drug testing and cell-based heart repair. Various strategies to foster cellular maturation provide some success, but fully matured cardiomyocytes are still to be achieved. Today, several hormones are recognized for their effects on cardiomyocyte proliferation, differentiation, and function. Here, we will discuss how the endocrine system impacts cardiomyocyte maturation. After detailing which features characterize a mature phenotype, we will contemplate hormones most promising to induce such a phenotype, the routes of their action, and experimental evidence for their significance in this process. Due to their pleiotropic effects, hormones might be not only valuable to improve in vitro heart cell generation but also beneficial for in vivo heart regeneration. Accordingly, we will also contemplate how the presented hormones might be exploited for hormone-based regenerative therapies.Graphical abstract[graphic not available: see fulltext]

Zhang, Yanwei; Cen, Jing; Yuan, Gaoliang; Jia, Zhao; Chen, Kangyong; Gao, Wa; Chen, Jing; Adamek, Mikolaj; Jia, Zhiying; Zou, Jun

doi: 10.1007/s00018-023-04860-2pmid: 37462751

DExD/H-box helicase (DDX) 5 belongs to the DExD/H-box helicase family. DDX family members play differential roles in the regulation of innate antiviral immune response. However, whether DDX5 is involved in antiviral immunity remains unclear. In this study, we found that DDX5 serves as a negative regulator of type I interferon (IFN) response. Overexpression of DDX5 inhibited IFN production induced by Spring viremia of carp virus (SVCV) and poly(I:C) and enhanced virus replication by targeting key elements of the RLR signaling pathway (MAVS, MITA, TBK1, IRF3 and IRF7). Mechanistically, DDX5 directly interacted with TBK1 to promote its autophagy-mediated degradation. Moreover, DDX5 was shown to block the interaction between TRAF3 and TBK1, hence preventing nuclear translocation of IRF3. Together, these data shed light on the roles of DDX5 in regulating IFN response.

Cui, Guina; Zhou, Jingxuan; Sun, Jiatong; Kou, Xiaochen; Su, Zhongqu; Xu, Yiliang; Liu, Tingjun; Sun, Lili; Li, Wenhui; Wu, Xuanning; Wei, Qingqing; Gao, Shaorong; Shi, Kerong

doi: 10.1007/s00018-023-04871-zpmid: 37470863

BackgroundAbundantly expressed factors in the oocyte cytoplasm can remarkably reprogram terminally differentiated germ cells or somatic cells into totipotent state within a short time. However, the mechanism of the different factors underlying the reprogramming process remains uncertain.MethodsOn the basis of Yamanaka factors OSKM induction method, MEF cells were induced and reprogrammed into iPSCs under conditions of the oocyte-derived factor Wdr82 overexpression and/or knockdown, so as to assess the reprogramming efficiency. Meanwhile, the cellular metabolism was monitored and evaluated during the reprogramming process. The plurpotency of the generated iPSCs was confirmed via pluripotent gene expression detection, embryoid body differentiation and chimeric mouse experiment.ResultsHere, we show that the oocyte-derived factor Wdr82 promotes the efficiency of MEF reprogramming into iPSCs to a greater degree than the Yamanaka factors OSKM. The Wdr82-expressing iPSC line showed pluripotency to differentiate and transmit genetic material to chimeric offsprings. In contrast, the knocking down of Wdr82 can significantly reduce the efficiency of somatic cell reprogramming. We further demonstrate that the significant suppression of oxidative phosphorylation in mitochondria underlies the molecular mechanism by which Wdr82 promotes the efficiency of somatic cell reprogramming. Our study suggests a link between mitochondrial energy metabolism remodeling and cell fate transition or stem cell function maintenance, which might shed light on the embryonic development and stem cell biology.

Panstruga, Ralph; Antonin, Wolfram; Lichius, Alexander

doi: 10.1007/s00018-023-04843-3pmid: 37418047

Many cell biological facts that can be found in dedicated scientific textbooks are based on findings originally made in humans and/or other mammals, including respective tissue culture systems. They are often presented as if they were universally valid, neglecting that many aspects differ—in part considerably—between the three major kingdoms of multicellular eukaryotic life, comprising animals, plants and fungi. Here, we provide a comparative cross-kingdom view on the basic cell biology across these lineages, highlighting in particular essential differences in cellular structures and processes between phyla. We focus on key dissimilarities in cellular organization, e.g. regarding cell size and shape, the composition of the extracellular matrix, the types of cell–cell junctions, the presence of specific membrane-bound organelles and the organization of the cytoskeleton. We further highlight essential disparities in important cellular processes such as signal transduction, intracellular transport, cell cycle regulation, apoptosis and cytokinesis. Our comprehensive cross-kingdom comparison emphasizes overlaps but also marked differences between the major lineages of the three kingdoms and, thus, adds to a more holistic view of multicellular eukaryotic cell biology.

Jiang, Hemin; Zheng, Shuai; Qian, Yu; Zhou, Yuncai; Dai, Hao; Liang, Yucheng; He, Yunqiang; Gao, Rui; Lv, Hui; Zhang, Jie; Xia, Zhiqing; Bian, Wenxuan; Yang, Tao; Fu, Qi

Limone, Adriana; Maggisano, Valentina; Sarnataro, Daniela; Bulotta, Stefania

doi: 10.1007/s00018-023-04844-2pmid: 37452879

The cellular prion protein (PrPC) is well-known for its involvement, under its pathogenic protease-resistant form (PrPSc), in a group of neurodegenerative diseases, known as prion diseases. PrPC is expressed in nervous system, as well as in other peripheral organs, and has been found overexpressed in several types of solid tumors. Notwithstanding, studies in recent years have disclosed an emerging role for PrPC in various cancer associated processes. PrPC has high binding affinity for 37/67 kDa laminin receptor (RPSA), a molecule that acts as a key player in tumorigenesis, affecting cell growth, adhesion, migration, invasion and cell death processes. Recently, we have characterized at cellular level, small molecules able to antagonize the direct PrPC binding to RPSA and their intracellular trafficking. These findings are very crucial considering that the main function of RPSA is to modulate key events in the metastasis cascade. Elucidation of the role played by PrPC/RPSA interaction in regulating tumor development, progression and response to treatment, represents a very promising challenge to gain pathogenetic information and discover novel specific biomarkers and/or therapeutic targets to be exploited in clinical settings. This review attempts to convey a detailed description of the complexity surrounding these multifaceted proteins from the perspective of cancer hallmarks, but with a specific focus on the role of their interaction in the control of proliferation, migration and invasion, genome instability and mutation, as well as resistance to cell death controlled by autophagic pathway.

Cao, Xuwen; Xie, Yusu; Yang, Hanwen; Sun, Peiqi; Xue, Beining; Garcia, L. Rene; Zhang, Liusuo

doi: 10.1007/s00018-023-04849-xpmid: 37450052

Dietary intake and nutrient composition regulate animal growth and development; however, the underlying mechanisms remain elusive. Our previous study has shown that either the mammalian deafness homolog gene tmc-1 or its downstream acetylcholine receptor gene eat-2 attenuates Caenorhabditis elegans development in a chemically defined food CeMM (C. elegans maintenance medium) environment, but the underpinning mechanisms are not well-understood. Here, we found that, in CeMM food environment, for both eat-2 and tmc-1 fast-growing mutants, several fatty acid synthesis and elongation genes were highly expressed, while many fatty acid β-oxidation genes were repressed. Accordingly, dietary supplementation of individual fatty acids, such as monomethyl branch chain fatty acid C17ISO, palmitic acid and stearic acid significantly promoted wild-type animal development on CeMM, and mutations in either C17ISO synthesis gene elo-5 or elo-6 slowed the rapid growth of eat-2 mutant. Tissue-specific rescue experiments showed that elo-6 promoted animal development mainly in the intestine. Furthermore, transcriptome and metabolome analyses revealed that elo-6/C17ISO regulation of C. elegans development may be correlated with up-regulating expression of cuticle synthetic and hedgehog signaling genes, as well as promoting biosynthesis of amino acids, amino acid derivatives and vitamins. Correspondingly, we found that amino acid derivative S-adenosylmethionine and its upstream metabolite methionine sulfoxide significantly promoted C. elegans development on CeMM. This study demonstrated that C17ISO, palmitic acid, stearic acid, S-adenosylmethionine and methionine sulfoxide inhibited or bypassed the TMC-1 and EAT-2-mediated attenuation of development via metabolic remodeling, and allowed the animals to adapt to the new nutritional niche.

Goldmann, Oliver; Medina, Eva

doi: 10.1007/s00018-023-04875-9pmid: 37480485

Staphylococcus aureus is an important cause of chronic infections resulting from the failure of the host to eliminate the pathogen. Effective S. aureus clearance requires CD4+ T cell-mediated immunity. We previously showed that myeloid-derived suppressor cells (MDSC) expand during staphylococcal infections and support infection chronicity by inhibiting CD4+ T cell responses. The aim of this study was to elucidate the mechanisms underlying the suppressive effect exerted by MDSC on CD4+ T cells during chronic S. aureus infection. It is well known that activated CD4+ T cells undergo metabolic reprogramming from oxidative metabolism to aerobic glycolysis to meet their increased bioenergetic requirements. In this process, pyruvate is largely transformed into lactate by lactate dehydrogenase with the concomitant regeneration of NAD+, which is necessary for continued glycolysis. The by-product lactate needs to be excreted to maintain the glycolytic flux. Using SCENITH (single-cell energetic metabolism by profiling translation inhibition), we demonstrated here that MDSC inhibit CD4+ T cell responses by interfering with their metabolic activity. MDSC are highly glycolytic and excrete large amount of lactate in the local environment that alters the transmembrane concentration gradient and prevent removal of lactate by activated CD4+ T. Accumulation of endogenous lactate impedes the regeneration of NAD+, inhibit NAD-dependent glycolytic enzymes and stop glycolysis. Together, the results of this study have uncovered a role for metabolism on MDSC suppression of CD4+ T cell responses. Thus, reestablishment of their metabolic activity may represent a mean to improve the functionality of CD4+ T cells during chronic S. aureus infection.