USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase

Fan, Yihui; Mao, Renfang; Ye, Yu; Liu, Shangfeng; Shi, Zhongcheng; Cheng, Jin; Zhang, Huiyuan; An, Lili; Zhao, Yanling; Xu, Xin; Chen, Zhenghu; Kogiso, Mari; Zhang, Dekai; Zhang, Hong; Zhang, Pumin; Jung, Jae U.; Li, Xiaonan; Xu, Guo‐Tong; Yang, Jianhua

doi:10.1084/jem.20122844

Cited by 153 publications

(150 citation statements)

References 50 publications

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“…Similar to human MAVS [10,44], fish MAVSs are constitutively expressed in all tissues examined [26,27,37,38]. However, inconsistent results are reported about its expression abundance in some tissues.…”

Section: Discussionmentioning

confidence: 92%

Fish MAVS is involved in RLR pathway-mediated IFN response

Zhang

et al. 2014

Fish & Shellfish Immunology

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Section: Discussionmentioning

confidence: 92%

Fish MAVS is involved in RLR pathway-mediated IFN response

Zhang

et al. 2014

Fish & Shellfish Immunology

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“…Of these, ubiquitin-specific proteases (USP) form the largest group that is characterized by the presence of a USP domain (32,33). USP21 was initially identified as a histone H2A deubiquitinase (34), but has been shown to regulate the deubiquitination of several other substrates including RIG-1, RIP1, and GATA-3 (35)(36)(37). USP21 is thought to modulate target protein stability by modulating E3 deubiquitinase activity, thereby affecting the transfer of ubiquitin from the E3 ligase to its target protein (36).…”

Section: Discussionmentioning

confidence: 99%

BEND3 represses rDNA transcription by stabilizing a NoRC component via USP21 deubiquitinase

Khan

Giri

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Ribosome biogenesis dictates the translational capacity of cells. Several mechanisms establish and maintain transcriptional output from eukaryotic ribosomal DNA (rDNA) loci. rDNA silencing is one such mechanism that ensures the inactivity and hence the maintenance of a silenced state of a subset of rRNA gene copies. Whereas oncogenic agents stimulate rRNA gene transcription, tumor suppressors decrease rRNA gene transcription. We demonstrate in mammalian cells that BANP, E5R, and Nac1 (BEN) domain 3 (BEND3), a quadruple BEN domain-containing protein, localizes in nucleoli and binds to ribosomal RNA gene promoters to help repress rRNA genes. Loss of BEND3 increases histone H3K4 trimethylation and, correspondingly, decreases rDNA promoter DNA methylation, consistent with a role for BEND3 in rDNA silencing. BEND3 associates with the nucleolar-remodeling complex (NoRC), and SUMOylated BEND3 stabilizes NoRC component TTF-1-interacting protein 5 via association with ubiquitin specific protease 21 (USP21) debiquitinase. Our results provide mechanistic insights into how the novel rDNA transcription repressor BEND3 acts together with NoRC to actively coordinate the establishment of rDNA silencing.

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“…Flag-TAK1 was generously gifted by Mingyu Lv (Jilin University, China). Flag-RIG-IN (CARD) was generously gifted by Jinhua Yang (Baylor College of Medicine, Houston, TX, USA) (71). Flag-MDA5-N (amino acids 1 to 213) was amplified from a template (purchased from Fitgene Company, Shanghai, China) and cloned into the SalI and BamHI sites of the VR1012 vector.…”

Section: Methodsmentioning

confidence: 99%

Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

Rui

Wang

et al. 2017

J Virol

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Coxsackievirus A16 (CV-A16), CV-A6, and enterovirus D68 (EV-D68) belong to the Picornaviridae family and are major causes of hand, foot, and mouth disease (HFMD) and pediatric respiratory disease worldwide. The biological characteristics of these viruses, especially their interplay with the host innate immune system, have not been well investigated. In this study, we discovered that the 3C pro proteins from CV-A16, CV-A6, and EV-D68 bind melanoma differentiation-associated gene 5 (MDA5) and inhibit its interaction with MAVS. Consequently, MDA5-triggered type I interferon (IFN) signaling in the retinoic acid-inducible gene I-like receptor (RLR) pathway was blocked by the CV-A16, CV-A6, and EV-D68 3C pro proteins. Furthermore, the CV-A16, CV-A6, and EV-D68 3C pro proteins all cleave transforming growth factor ␤-activated kinase 1 (TAK1), resulting in the inhibition of NF-B activation, a host response also critical for Toll-like receptor (TLR)-mediated signaling. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed novel mechanisms to subvert host innate immune responses by targeting key factors in the RLR and TLR pathways. Blocking the ability of 3C pro proteins from diverse enteroviruses and coxsackieviruses to interfere with type I IFN induction should restore IFN antiviral function, offering a potential novel antiviral strategy.IMPORTANCE CV-A16, CV-A6, and EV-D68 are emerging pathogens associated with hand, foot, and mouth disease and pediatric respiratory disease worldwide. The pathogenic mechanisms of these viruses are largely unknown. Here we demonstrate that the CV-A16, CV-A6, and EV-D68 3C pro proteins block MDA5-triggered type I IFN induction. The 3C pro proteins of these viruses bind MDA5 and inhibit its interaction with MAVS. In addition, the CV-A16, CV-A6, and EV-D68 3C pro proteins cleave TAK1 to inhibit the NF-B response. Thus, our data demonstrate that circulating HFMDassociated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed a mechanism to subvert host innate immune responses by simultaneously targeting key factors in the RLR and TLR pathways. These findings indicate the potential merit of targeting the CV-A16, CV-A6, and EV-D68 3C pro proteins as an antiviral strategy.KEYWORDS MDA5, TAK1, MAVS, 3C protease, CV-A16, CV-A6, EV-D68, HFMD, innate immune response

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USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase

Abstract: The deubiquitinase USP21 targets RIG-I for deubiquitination, thus dampening interferon production and activation of IFN-responsive genes in response to RNA viruses.

Cited by 153 publications

References 50 publications

Fish MAVS is involved in RLR pathway-mediated IFN response

Fish MAVS is involved in RLR pathway-mediated IFN response

BEND3 represses rDNA transcription by stabilizing a NoRC component via USP21 deubiquitinase

Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

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