Syndecan-4 negatively regulates antiviral signalling by mediating RIG-I deubiquitination via CYLD

Lin, Wei; Zhang, Jing; Lin, Haiyan; Li, Zexing; Sun, Xiaofeng; Di, Xin; Yang, Meng; Sun, Liwei; Li, Lin; Wang, Hongmei; Chen, Dahua; Sun, Qing

doi:10.1038/ncomms11848

Cited by 37 publications

(41 citation statements)

References 39 publications

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“…However, this approach was unsuccessful because treatment with proteasome inhibitors was harmful in this cell type, and viability of the cells markedly decreased viability in this cell type (data not shown). To examine the ubiquitination of target molecules, most of the studies have used co-overexpression of constructs for tagged-ubiquitin and another tagged-target molecule in immortalized cell lines [23]. However, such overexpression experiments are impossible in primary culture of MCs, because the number of cells are limited and the transfection of large constructs are harmful for these primary culture cells.…”

Section: Discussionmentioning

confidence: 99%

Cylindromatosis (CYLD), a Deubiquitinase, Attenuates Inflammatory Signaling Pathways by Activating Toll-Like Receptor 3 in Human Mesangial Cells

Imaizumi

Hayakari

Watanabe³

et al. 2017

Kidney Blood Press Res

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Background/Aims: Cylindromatosis (CYLD), a deubiquitinase, negatively regulates nuclear factor-κB in various cells. However, its potential roles in glomerular inflammation remain unclear. Because the activation of the Toll-like receptor 3 (TLR3)/type I interferon (IFN) pathways plays a pivotal role in chronic kidney diseases (CKD), we examined the role of CYLD in the TLR3 signaling in cultured human mesangial cells (MCs). Methods: We stimulated CYLD-silenced MCs with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of dsRNA, and studied representative TLR3/IFN-β pathways (i.e., TLR3/IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5, and TLR3/IFN-β/melanoma differentiation associated gene 5 (MDA5)/CXCL10 axes) using RT-PCR, western blotting, and ELISA. We also used immunofluorescence staining and microscopy to examine mesangial CYLD expression in biopsied specimens from patients with CKD. Results: CYLD silencing resulted in an increase of poly IC-induced RIG-I and MDA5 protein levels and increased CCL5 and CXCL10 mRNA and protein expression, but unexpectedly decreased mRNA expressions of RIG-I and MDA5. Interestingly, CYLD silencing did not affect IFN-β or the phosphorylated STAT1 (signal transducers and activator of transcription protein 1). CYLD was highly expressed in biopsied specimens from patients with proliferative lupus nephritis (LN). Conclusion: CYLD inhibits post-transcriptional regulation of RIG-I and MDA5 expression following TLR3 activation in MCs. CYLD may be involved in the pathogenesis of CKD, especially pathogenesis of LN.

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Section: Discussionmentioning

confidence: 99%

Cylindromatosis (CYLD), a Deubiquitinase, Attenuates Inflammatory Signaling Pathways by Activating Toll-Like Receptor 3 in Human Mesangial Cells

Imaizumi

Hayakari

Watanabe³

et al. 2017

Kidney Blood Press Res

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“…The tumor suppressor protein cylindromatosis (CYLD) removes K63-linked pUb chains from RIG-I as well as TBK1 and IKKϵ to inhibit the IRF3 response, serving as a pathway negative regulator (60). Syndecan-4, a newly identified negative regulator of RIG-I, functions through attracting CYLD to RIG-I complex, thus potentiating the K63-mediated deubiquitination of RIG-I (61). In addition, the ubiquitin-specific protease (USP) family members, such as USP3 and USP21, were also identified as inhibitors of RIG-I activation by deubiqutinating RIG-I (62,63).…”

Section: Posttranslational Control Of Rig-i Ubiquitinationmentioning

confidence: 99%

Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity

2017

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Innate immunity is the first line of defense against invading pathogens. Rapid and efficient detection of pathogen-associated molecular patterns via pattern-recognition receptors is essential for the host to mount defensive and protective responses. Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. Upon viral RNA recognition, RIG-I recruits the mitochondrial adaptor protein mitochondrial antiviral signaling protein, which leads to a signaling cascade that coordinates the induction of type I interferons (IFNs), as well as a large variety of antiviral interferon-stimulated genes. The RIG-I activation is tightly regulated via various posttranslational modifications for the prevention of aberrant innate immune signaling. By contrast, viruses have evolved mechanisms of evasion, such as sequestrating viral structures from RIG-I detections and targeting receptor or signaling molecules for degradation. These virus–host interactions have broadened our understanding of viral pathogenesis and provided insights into the function of the RIG-I pathway. In this review, we summarize the recent advances regarding RIG-I pathogen recognition and signaling transduction, cell-intrinsic control of RIG-I activation, and the viral antagonism of RIG-I signaling.

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“…The level of antiviral cytokines is significantly higher in USP21/SDC4-deficient mice. It should be noted that USP21/SDC4deficient mice are more resistant to viral infection as compared with the control mice (Fan et al, 2014;Lin et al, 2016). It can thus be inferred that the depression of endogenous negative regulators of type I IFN exhibits a potential antiviral effect.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, a cellular protein antagonizes the activation of RIG-I and participates in the innate immune response during viral infection. Such as Syndecan-4 (SDC4) and NOD-like receptor family CARD domain containing 5 (NLRC5) protein can interact with RIG-I to negatively regulate type I IFN antiviral response (Cui et al, 2010;Lin et al, 2016). The level of antiviral cytokines is significantly higher in USP21/SDC4-deficient mice.…”

Section: Introductionmentioning

confidence: 99%

Cellular protein GLTSCR2: A valuable target for the development of broad-spectrum antivirals

Dong

Wang

et al. 2017

Antiviral Research

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Viral infection induces translocation of the nucleolar protein GLTSCR2 from the nucleus to the cytoplasm, resulting in attenuation of the type I interferon IFN-β. Addressing the role of GLTSCR2 in viral replication, we detect that knocking down GLTSCR2 by shRNAs results in significant suppression of viral replication in mammalian and chicken cells. Injection of chicken embryo with the GLTSCR2-specific shRNA-1370 simultaneously or 24 h prior to infection with Newcastle disease virus (NDV) substantially reduces viral replication in chicken embryo fibroblasts. Injection of shRNA-1370 into chicken embryo also reduces the replication of avian influenza virus (AIV). In contrast, GLTSCR2-derived protein G4-T, forming α-helical dimers, increases replication of seven various DNA and RNA viruses in cells. Our studies reveal that alteration of the function of cellular GLTSCR2 plays a role in supporting viral replication. GLTSCR2 should be seriously considered as a therapeutic target for developing broad spectrum antiviral agents to effectively control viral infection.

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Syndecan-4 negatively regulates antiviral signalling by mediating RIG-I deubiquitination via CYLD

Cited by 37 publications

References 39 publications

Cylindromatosis (CYLD), a Deubiquitinase, Attenuates Inflammatory Signaling Pathways by Activating Toll-Like Receptor 3 in Human Mesangial Cells

Cylindromatosis (CYLD), a Deubiquitinase, Attenuates Inflammatory Signaling Pathways by Activating Toll-Like Receptor 3 in Human Mesangial Cells

Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity

Cellular protein GLTSCR2: A valuable target for the development of broad-spectrum antivirals

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