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Review
. 2019 Jul 18:2019:2128410.
doi: 10.1155/2019/2128410. eCollection 2019.

The Role of Deubiquitinases in Oncovirus and Host Interactions

Yueshuo Li  1   2   3 , Feng Shi  1   2   3 , Jianmin Hu  1   2   3 , Longlong Xie  1   2   3 , Ann M Bode  4 , Ya Cao  1   2   3   5   6   7
Affiliations
Review

The Role of Deubiquitinases in Oncovirus and Host Interactions

Yueshuo Li et al. J Oncol. .

Abstract

Infection-related cancer comprises one-sixth of the global cancer burden. Oncoviruses can directly or indirectly contribute to tumorigenesis. Ubiquitination is a dynamic and reversible posttranslational modification that participates in almost all cellular processes. Hijacking of the ubiquitin system by viruses continues to emerge as a central theme around the viral life cycle. Deubiquitinating enzymes (DUBs) maintain ubiquitin homeostasis by removing ubiquitin modifications from target proteins, thereby altering protein function, stability, and signaling pathways, as well as acting as key mediators between the virus and its host. In this review, we focus on the multiple functions of DUBs in RIG-I-like receptors (RLRs) and stimulator of interferon genes (STING)-mediated antiviral signaling pathways, oncoviruses regulation of NF-κB activation, oncoviral life cycle, and the potential of DUB inhibitors as therapeutic strategies.

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Conflict of interest statement

The authors have no conflicts of interest.

Figures

Figure 1
Figure 1
DUBs participate in antiviral innate immunity. During virus infection, K63-linked polyubiquitination of RLRs promotes their interaction with MAVS and signal transmission. USP15 inhibits K48-ubiquitination of RNA sensor RIG-I to inhibit RIG-I degradation; A20, CYLD, USP3, and USP21 inhibit K63-ubiquitination of RIG-I to negatively regulate RIG-I activation. USP3 inhibits K63 ubiquitination of MDA5 to inhibit its activation. RIG-I and MDA5 bind to and activate MAVS. Activated MAVS works as a scaffold to recruit various TRAFs, leading to TBK1/IƘB kinase Ɛ (IKK-Ɛ)-mediated phosphorylation and nuclear translocation of IRF3 and IRF7, and production of IFNs and OTUD1 stabilizes MAVS by removing K48-ubiquitination. Deubiquitinases OTUB1/2, MYSM1, and DUBA inhibit K63-linked ubiquitination of TRAF3 or TRAF6 and negatively regulate IFNs production. HSV infection can recruit USP21 to deubiquitinate the K27/63-linked polyubiquitin chain on STING. USP13 removes K27-linked polyubiquitin chains from STING and thereby impairs the recruitment of TBK1 to reduce the antiviral immune response against DNA viruses. USP18 recruits USP20 in an enzymatic activity-independent manner and facilitates USP20 to remove K33- and K48-linked ubiquitin chains from STING, thereby preventing degradation of STING caused by DNA virus infection. USP7 interacts with TRIM27 and removes its K48-linked polyubiquitination, promoting the degradation of TBK1. USP1 and UAF1 inhibit K48 polyubiquitin chains to stabilize TBK1 contributing to IFNs production.
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