COVID-19 is caused by SARS-CoV-2 infection and characterized by diverse clinical symptoms. Type I interferon (IFN-I) production is impaired and severe cases lead to ARDS and widespread coagulopathy. We propose that COVID-19 pathophysiology is initiated by SARS-CoV-2 gene products, the NSP1 and ORF6 proteins, leading to a catastrophic cascade of failures. These viral components induce signal transducer and activator of transcription 1 (STAT1) dysfunction and compensatory hyperactivation of STAT3. In SARS-CoV-2-infected cells, a positive feedback loop established between STAT3 and plasminogen activator inhibitor-1 (PAI-1) may lead to an escalating cycle of activation in common with the interdependent signaling networks affected in COVID-19. Specifically, PAI-1 upregulation leads to coagulopathy characterized by intravascular thrombi. Overproduced PAI-1 binds to TLR4 on macrophages, inducing the secretion of proinflammatory cytokines and chemokines. The recruitment and subsequent activation of innate immune cells within an infected lung drives the destruction of lung architecture, which leads to the infection of regional endothelial cells and produces a hypoxic environment that further stimulates PAI-1 production. Acute lung injury also activates EGFR and leads to the phosphorylation of STAT3. COVID-19 patients’ autopsies frequently exhibit diffuse alveolar damage (DAD) and increased hyaluronan (HA) production which also leads to higher levels of PAI-1. COVID-19 risk factors are consistent with this scenario, as PAI-1 levels are increased in hypertension, obesity, diabetes, cardiovascular diseases, and old age. We discuss the possibility of using various approved drugs, or drugs currently in clinical development, to treat COVID-19. This perspective suggests to enhance STAT1 activity and/or inhibit STAT3 functions for COVID-19 treatment. This might derail the escalating STAT3/PAI-1 cycle central to COVID-19.

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Methylation of EZH2 by PRMT1 regulates its stability and promotes breast cancer metastasis

Li, Zhongwei; Wang, Diandian; Lu, Jun; Huang, Baiqu; Wang, Yibo; Dong, Meichen; Fan, Dongmei; Li, Hongyuan; Gao, Yanyan; Hou, Pingfu; Li, Minle; Liu, Hui; Pan, Zhen-Qiang; Zheng, Junnian; Bai, Jin

2020 Cell Death & Differentiation

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SUGT1 controls susceptibility to HIV-1 infection by stabilizing microtubule plus-ends

Allouch, Awatef; Di Primio, Cristina; Paoletti, Audrey; Lê-Bury, Gabrielle; Subra, Frédéric; Quercioli, Valentina; Nardacci, Roberta; David, Annie; Saïdi, Héla; Cereseto, Anna; Ojcius, David M.; Montagnac, Guillaume; Niedergang, Florence; Pancino, Gianfranco; Saez-Cirion, Asier;

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The miR-92a-2-5p in exosomes from macrophages increases liver cancer cells invasion via altering the AR/PHLPP/p-AKT/β-catenin signaling

Liu, Guodong; Ouyang, Xiwu; Sun, Yin; Xiao, Yao; You, Bosen; Gao, Yuan; Yeh, Shuyuan; Li, Yixiong; Chang, Chawnshang

2020 Cell Death & Differentiation

doi: 10.1038/s41418-020-0575-3pmid: 32587378

Early studies indicated that the androgen receptor (AR) might play important roles in the regulating of the initiation and progression of hepatocellular carcinoma (HCC), but its linkage to the surrounding macrophages and their impacts on the HCC progression remain unclear. Here we found that macrophages in liver cancer might function via altering the microRNA, miR-92a-2-5p, in exosomes to decrease liver cancer cells AR expression, which might then lead to increase the liver cancer cells invasion. Mechanism dissection revealed that miR-92a-2-5p from the exosomes could target the 3′UTR of AR mRNA to suppress AR translation, altering the PHLPP/p-AKT/β-catenin signaling to increase liver cancer cells invasion. Preclinical studies demonstrated that targeting this newly identified signaling with miR-92a-2-5p inhibitors led to suppress liver cancer progression. Together, these findings suggest that macrophages in the liver cancer tumor microenvironment may function via exosomes to regulate liver cancer progression, and targeting this newly identified macrophages/exosomes-miR-92a-2-5p/AR/PHLPP/p-AKT/β-catenin signaling may help in the development of novel treatment strategies to better suppress liver cancer progression.

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BRPF3-HUWE1-mediated regulation of MYST2 is required for differentiation and cell-cycle progression in embryonic stem cells

Cho, Hye In; Kim, Min Seong; Lee, Jina; Yoo, Byong Chul; Kim, Kyung Hee; Choe, Kwang-Min; Jang, Yeun Kyu

2020 Cell Death and Differentiation

doi: 10.1038/s41418-020-0577-1pmid: 32555450

Brpf-histone acetyltransferase (HAT) complexes have important roles in embryonic development and regulating differentiation in ESCs. Among Brpf family, Brpf3 is a scaffold protein of Myst2 histone acetyltransferase complex that plays crucial roles in gene regulation, DNA replication, development as well as maintaining pluripotency in embryonic stem cells (ESCs). However, its biological functions in ESCs are not elucidated. In this study, we find out that Brpf3 protein level is critical for Myst2 stability and E3 ligase Huwe1 functions as a novel negative regulator of Myst2 via ubiquitin-mediated degradation. Importantly, Brpf3 plays an antagonistic role in Huwe1-mediated degradation of Myst2, suggesting that protein–protein interaction between Brpf3 and Myst2 is required for retaining Myst2 stability. Further, Brpf3 overexpression causes the aberrant upregulation of Myst2 protein levels which in turn induces the dysregulated cell-cycle progression and also delay of early embryonic development processes such as embryoid-body formation and lineage commitment of mouse ESCs. The Brpf3 overexpression-induced phenotypes can be reverted by Huwe1 overexpression. Together, these results may provide novel insights into understanding the functions of Brpf3 in proper differentiation as well as cell-cycle progression of ESCs via regulation of Myst2 stability by obstructing Huwe1-mediated ubiquitination. In addition, we suggest that this is a useful report which sheds light on the function of an unknown gene in ESC field.

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An oncogenic viral interferon regulatory factor upregulates CUB domain-containing protein 1 to promote angiogenesis by hijacking transcription factor lymphoid enhancer-binding factor 1 and metastasis suppressor CD82

Li, Wan; Wang, Qingxia; Qi, Xiaoyu; Lu, Hongmei; Chen, Yuheng; Shi, Jiale; Wang, Fei; Wang, Ziyu; Lu, Yao; Lu, Zhongmou; Yan, Qin; Wang, Cong; Gao, Shou-Jiang; Lu, Chun

2020 Cell Death & Differentiation

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SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium

Terakawa, Jumpei; Serna, Vanida A.; Nair, Devi M.; Sato, Shigeru; Kawakami, Kiyoshi; Radovick, Sally; Maire, Pascal; Kurita, Takeshi

2020 Cell Death & Differentiation

doi: 10.1038/s41418-020-0579-zpmid: 32572167

During female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of the vagina and ectocervix, when the expression of ΔNp63 transcription factor is induced by mesenchymal cells. The absence of ΔNp63 expression leads to adenosis, the putative precursor of vaginal adenocarcinoma. Our previous studies with genetically engineered mouse models have established that fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP)/SMAD, and activin A/runt-related transcription factor 1 (RUNX1) signaling pathways are independently required for ΔNp63 expression in Müllerian duct epithelium (MDE). Here, we report that sine oculis homeobox homolog 1 (SIX1) plays a critical role in the activation of ΔNp63 locus in MDE as a downstream transcription factor of mesenchymal signals. In the developing mouse reproductive tract, SIX1 expression was restricted to MDE within the future cervix and vagina. SIX1 expression was totally absent in SMAD4 null MDE and was reduced in RUNX1 null and FGFR2 null MDE, indicating that SIX1 is under the control of vaginal mesenchymal factors: BMP4, activin A and FGF7/10. Furthermore, Six1, Runx1, and Smad4 gene-dose-dependently activated ΔNp63 expression in MDE within the vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) inhibits activation of ΔNp63 locus in MDE by transcriptionally repressing SIX1 and RUNX1 in the vaginal fornix.

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Yin Yang 1 is required for PHD finger protein 20-mediated myogenic differentiation in vitro and in vivo

Lee, Hyunji; Hong, Youngeun; Kong, Gyeyeong; Lee, Dong Hoon; Kim, Minhee; Tran, Quangdon; Cho, Hyeonjeong; Kim, Chaeyeong; Park, Sungjin; Kim, Seon-Hwan; Kwon, So Hee; Park, Jongsun; Park, Jisoo

2020 Cell Death & Differentiation

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LRIK interacts with the Ku70–Ku80 heterodimer enhancing the efficiency of NHEJ repair

Wang, Dan; Zhou, Zheng; Wu, Erzhong; Ouyang, Can; Wei, Guifeng; Wang, Yunfei; He, Dandan; Cui, Ya; Zhang, Dongdong; Chen, Xiaomin; Reed, Simon H.; Luo, Jianjun; Chen, Runsheng

2020 Cell Death & Differentiation

doi: 10.1038/s41418-020-0581-5

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Open Access Collection

Loss of Ryanodine Receptor 2 impairs neuronal activity-dependent remodeling of dendritic spines and triggers compensatory neuronal hyperexcitability

Bertan, Fabio; Wischhof, Lena; Sosulina, Liudmila; Mittag, Manuel; Dalügge, Dennis; Fornarelli, Alessandra; Gardoni, Fabrizio; Marcello, Elena; Di Luca, Monica; Fuhrmann, Martin; Remy, Stefan; Bano, Daniele; Nicotera, Pierluigi

2020 Cell Death & Differentiation

doi: 10.1038/s41418-020-0584-2pmid: 32641776

Dendritic spines are postsynaptic domains that shape structural and functional properties of neurons. Upon neuronal activity, Ca2+ transients trigger signaling cascades that determine the plastic remodeling of dendritic spines, which modulate learning and memory. Here, we study in mice the role of the intracellular Ca2+ channel Ryanodine Receptor 2 (RyR2) in synaptic plasticity and memory formation. We demonstrate that loss of RyR2 in pyramidal neurons of the hippocampus impairs maintenance and activity-evoked structural plasticity of dendritic spines during memory acquisition. Furthermore, post-developmental deletion of RyR2 causes loss of excitatory synapses, dendritic sparsification, overcompensatory excitability, network hyperactivity and disruption of spatially tuned place cells. Altogether, our data underpin RyR2 as a link between spine remodeling, circuitry dysfunction and memory acquisition, which closely resemble pathological mechanisms observed in neurodegenerative disorders.

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doi: 10.1038/s41418-020-00615-9pmid: 32895488

Enhancer of zeste homolog 2 (EZH2), a key histone methyltransferase and EMT inducer, is overexpressed in diverse carcinomas, including breast cancer. However, the molecular mechanisms of EZH2 dysregulation in cancers are still largely unknown. Here, we discover that EZH2 is asymmetrically dimethylated at R342 (meR342-EZH2) by PRMT1. meR342-EZH2 was found to inhibit the CDK1-mediated phosphorylation of EZH2 at T345 and T487, thereby attenuating EZH2 ubiquitylation mediated by the E3 ligase TRAF6. We also demonstrate that meR342-EZH2 resulted in a decrease in EZH2 target gene expression, but an increase in breast cancer cell EMT, invasion and metastasis. Moreover, we confirm the positive correlations among PRMT1, meR342-EZH2 and EZH2 expression in the breast cancer tissues. Finally, we report that high expression levels of meR342-EZH2 predict a poor clinical outcome in breast cancer patients. Our findings may provide a novel diagnostic target and promising therapeutic target for breast cancer metastasis.

2020 Cell Death & Differentiation

doi: 10.1038/s41418-020-0573-5pmid: 32514048

Understanding the viral–host cell interface during HIV-1 infection is a prerequisite for the development of innovative antiviral therapies. Here we show that the suppressor of G2 allele of skp1 (SUGT1) is a permissive factor for human immunodeficiency virus (HIV)-1 infection. Expression of SUGT1 increases in infected cells on human brain sections and in permissive host cells. We found that SUGT1 determines the permissiveness to infection of lymphocytes and macrophages by modulating the nuclear import of the viral genome. More importantly, SUGT1 stabilizes the microtubule plus-ends (+MTs) of host cells (through the modulation of microtubule acetylation and the formation of end-binding protein 1 (EB1) comets). This effect on microtubules favors HIV-1 retrograde trafficking and replication. SUGT1 depletion impairs the replication of HIV-1 patient primary isolates and mutant virus that is resistant to raltegravir antiretroviral agent. Altogether our results identify SUGT1 as a cellular factor involved in the post-entry steps of HIV-1 infection that may be targeted for new therapeutic approaches.

doi: 10.1038/s41418-020-0578-0pmid: 32555380

Kaposi’s sarcoma (KS), a highly angiogenic and invasive vascular tumor, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) contributes to KSHV-induced cell motility (PLoS Pathog. 15:e1007578, 2019). However, the role of vIRF1 in KSHV-induced angiogenesis remains unknown. Here, using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice, we show that vIRF1 promotes angiogenesis by upregulating CUB domain (for complement C1r/C1s, Uegf, Bmp1) containing protein 1 (CDCP1). Mechanistically, vIRF1 enhances the expression of transcription factor lymphoid enhancer-binding factor 1 (Lef1) and binds to Lef1 to promote CDCP1 transcription. Meanwhile, vIRF1 degrades metastasis suppressor CD82 through an ubiquitin–proteasome pathway by recruiting E3 ubiquitin ligase AMFR to CD82, which protects CDCP1 from CD82-mediated, palmitoylation-dependent degradation. CDCP1 activates AKT signaling, which is required for vIRF1-induced cell motility but not angiogenesis. Our results illustrate that, by hijacking Lef1 and CD82, vIRF1 upregulates CDCP1 to promote angiogenesis and cell invasion. These novel findings demonstrate the vIRF1 targets multiple cellular proteins and pathways to promote the pathogenesis of KS, which could be attractive therapeutic targets for KSHV-induced malignancies.

doi:

10.1038/s41418-020-0580-6

pmid:

32555448

The development of skeletal muscle requires progression of a highly ordered cascade of events comprising myogenic lineage commitment, myoblast proliferation, and terminal differentiation. The process of myogenesis is controlled by several myogenic transcription factors that act as terminal effectors of signaling cascades and produce appropriate developmental stage-specific transcripts. PHD finger protein 20 (PHF20) is a multidomain protein and subunit of a lysine acetyltransferase complex that acetylates histone H4 and p53, but its function is unclear. Notably, it has been reported that PHF20 knockout mice die shortly after birth and display a wide variety of phenotypes within the skeletal and hematopoietic systems. Therefore, the putative role of PHF20 in myogenic differentiation was further investigated. In the present study, we found that protein and mRNA expression levels of PHF20 were decreased during myogenic differentiation in C2C12 cells. At the same time, Yin Yang 1 (YY1) was also decreased during myogenic differentiation. PHF20 overexpression increased YY1 expression during myogenic differentiation, together with a delay in MyoD expression. PHF20 expression enhanced the transcriptional activity of YY1 while shRNA-mediated depletion of PHF20 resulted in the reduction of YY1 promoter activity in C2C12 cells. In addition, PHF20 directly bounds to the YY1 promoter in C2C12 cells. In a similar manner, YY1 expression was elevated while myosin heavy chain expression was decreased in PHF20 transgenic (TG) mice. Histological analysis revealed abnormalities in the shape and length of muscles in PHF20-TG mice. Furthermore, PHF20-TG muscles slowly regenerated after cardiotoxin injection, indicating that PHF20 affected muscle differentiation and regeneration after injury in vivo. Taken together, these results suggested that PHF20 plays an important role in myogenic differentiation by regulating YY1.

pmid:

32587379

Despite recent advances in our understanding of the function of long noncoding RNAs (lncRNAs), their roles and functions in DNA repair pathways remain poorly understood. By screening a panel of uncharacterized lncRNAs to identify those whose transcription is induced by double-strand breaks (DSBs), we identified a novel lncRNA referred to as LRIK that interacts with Ku, which enhances the ability of the Ku heterodimer to detect the presence of DSBs. Here, we show that depletion of LRIK generates significantly enhanced sensitivity to DSB-inducing agents and reduced DSB repair efficiency. In response to DSBs, LRIK enhances the recruitment of repair factors at DSB sites and facilitates γH2AX signaling. Our results demonstrate that LRIK is necessary for efficient repairing DSBs via nonhomologous end-joining pathway.