USP19 Suppresses Cellular type I Interferon Signaling by Targeting TRAF3 for Deubiquitination

Gu, Zhiwen; Shi, Weifeng; Zhang, Li; Hu, Zhongliang; Xu, Chao

doi:10.2217/fmb-2017-0006

Cited by 26 publications

(34 citation statements)

References 52 publications

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“…Therefore, we speculate that USP4 plays an essential role in antiviral immune response. USP4 has previously been confirmed to target TRAF2 and TRAF6 for deubiquitination and it has been established that USP4 inhibits TNFα-induced cancer cell migration 35 . It was confirmed that USP4 associates with TRAF2 and TRAF6, consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

“…The USPs are the biggest subfamily with more than 50 members 33 , with some of them known to regulate antiviral immune responses 28 , 34 , 35 . Previous studies have indicated that EV71 infection induces the up-regulation of USP19, which negatively regulates the antiviral type I interferon signalling by removing K-63 polyubiquitin chains from TRAF3 35 . In this study, 88 DUBs were screened in EV71-infected RD cells, and the expression of USP4 was found to be remarkably decreased at 8 h p.i.…”

Section: Discussionmentioning

confidence: 99%

“…Deubiquitination assays were conducted as described previously 35 . In brief, for analysing the ubiquitination of TRAF6, HEK293T cells were co-transfected with either Flag-TRAF6, HA-tagged ubiquitin or its mutants, with or without HA-USP4 for 48 h. Whole cell lysates were incubated with a Flag antibody for 1 h at 4 °C, which was followed by incubation with Protein A/G plus agarose beads overnight at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

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USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication

Peng

Zhang

et al. 2018

Sci Rep

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Retinoic acid-inducible gene I-like receptor (RLR) is one of the most important pattern recognition receptors of the innate immune system that detects positive and/or negative stranded RNA viruses. Subsequently, it stimulates downstream transcription of interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) inducing the production of interferons (IFNs) and inflammatory cytokines. Tumour necrosis factor receptor associated factor 6 (TRAF6) is a key protein involved in the RLR-mediated antiviral signalling pathway, recruiting additional proteins to form a multiprotein complex capable of activating the NF-κB inflammatory pathway. Despite TRAF6 playing an important role in regulating host immunity and viral infection, the deubiquitination of TRAF6 induced by viral infection remains elusive. In this study, we found that enterovirus 71 (EV71) infection attenuated the expression of Ubiquitin-specific protease 4 (USP4) in vitro and in vivo, while overexpression of USP4 significantly suppressed EV71 replication. Furthermore, it was found that EV71 infection reduced the RLR signalling pathway and enhanced the degradation of TRAF6. USP4 was also found to interact with TRAF6 and positively regulate the RLR-induced NF-κB signalling pathway, inhibiting the replication of EV71. Therefore, as a novel positive regulator of TRAF6, USP4 plays an essential role in EV71 infection by deubiquitinating K48-linked ubiquitin chains.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication

Peng

Zhang

et al. 2018

Sci Rep

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“…Helicase RIG-I belongs to the retinoic acidinducible gene I-like receptor (RLR) family, which recognizes single/double-stranded RNA and can be activated upon N-terminal 63K polyubiquitination [66]. As a key regulator of this step, cellular DUB USP14 has been shown to directly deubiquitinylate RIG-I, which has the effect of enhancing the replication of vesicular stomatitis virus (VSV) [67]. Similarly, DUB USP19 promotes replication of enterovirus type 71 (EV71) by removing the K63 polyubiquitin chains from TRAF3 (thereby suppressing cellular type I IFN-γ signaling) [68] and deubiquitinating Beclin-1, which leads to the activation of autophagy and subsequent inhibition of TBK1/IRF3 activation and the immune response [69].…”

Section: Ubiqitination and Its Interplay With Acetylation In Neutralimentioning

confidence: 99%

Lysine-specific post-translational modifications of proteins in the life cycle of viruses

et al. 2019

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The process of protein post-translational modifications (PTM) is one of the critical mechanisms of regulation of many cellular processes, which makes it an attractive target for various viruses. Since viruses cannot replicate on their own, they have developed unique abilities to alter metabolic and signaling cell pathways, including protein PTMs, to ensure faithful replication of their genomes. This review describes several ways of how lysine-specific PTMs are used by various viruses to ensure its successful invasion and replication. Covalent modifications like acetylation, ubiquitination, and methylation form a complex system of reversible and often competing modifications, which adds an additional level of complexity to the system of regulation of the activity of host proteins involved in viral replication and propagation. In furthering these, we also describe the manner in which PTM pathways can also be accosted by various types of viruses to neutralize the host's cellular mechanisms for anti-viral protection and highlight key areas for future therapeutic targeting and design.

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“…Meanwhile, many cellular DUBs negatively regulate type I IFN signaling pathways. For example, USP3, USP38, and USP19 target RIG-I, TBK1, and TRAF3 for deubiquitination, respectively, thereby blocking the activation of type I IFN signaling pathways (Cui et al, 2014;Gu et al, 2017;Lin et al, 2016). DUB activity also has been demonstrated in many bacteria and viruses, such as Salmonella enterica serovar Typhimurium, FMDV, PRRSV, herpesviruses, coronaviruses, and bunyaviruses, and DUB Fig.…”

mentioning

confidence: 99%

Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

et al. 2018

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The mechanisms that enable Seneca Valley Virus (SVV) to escape the host innate immune response are not well known. Previous studies demonstrated that SVV 3C pro suppresses innate immune responses by cleavage of host proteins and degradation of IRF3 and IRF7 protein expression. Here, we showed that SVV 3C protease (3C pro ) has deubiquitinating activity. Overexpressed 3C pro inhibits the ubiquitination of cellular substrates, acting on both lysine-48-and lysine-63-linked polyubiquitin chains. SVV infection also possessed deubiquitinating activity. The ubiquitin-proteasome system was significantly involved in SVV replication. Furthermore, 3C pro inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-β and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3C pro abrogated its deubiquitinating activity and the ability of 3C pro to block IFN-β induction.Together, our results demonstrate a novel mechanism developed by SVV 3C pro to promote viral replication, and may also provide a novel strategy for improving ubiquitination-based therapy.

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USP19 Suppresses Cellular type I Interferon Signaling by Targeting TRAF3 for Deubiquitination

Abstract: This work suggests that USP19 is a previously unrecognized regulator employed by EV71 to evade host antiviral defenses.

Cited by 26 publications

References 52 publications

USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication

USP4 positively regulates RLR-induced NF-κB activation by targeting TRAF6 for K48-linked deubiquitination and inhibits enterovirus 71 replication

Lysine-specific post-translational modifications of proteins in the life cycle of viruses

Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

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