The Role of Deubiquitinases in Oncovirus and Host Interactions

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.