USP13 negatively regulates antiviral responses by deubiquitinating STING

Abstract

STING (also known as MITA) is critical for host defence against viruses and the activity of STING is regulated by ubiquitination. However, the deubiquitination of STING is not fully understood. Here, we show that ubiquitin-specific protease 13 (USP13) is a STING-interacting protein that catalyses deubiquitination of STING. Knockdown or knockout of USP13 potentiates activation of IRF3 and NF-κB and expression of downstream genes after HSV-1 infection or transfection of DNA ligands. USP13 deficiency results in impaired replication of HSV-1. Consistently, USP13 deficient mice are more resistant than wild-type littermates to lethal HSV-1 infection. Mechanistically, USP13 deconjugates polyubiquitin chains from STING and prevents the recruitment of TBK1 to the signalling complex, thereby negatively regulating cellular antiviral responses. Our study thus uncovers a function of USP13 in innate antiviral immunity and provides insight into the regulation of innate immunity.

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

“…22,23 Although around a half dozen E3s have been reported to catalyze K48-linked ubiquitination and degradation of MAVS, it remained unknown how deubiquitination of MAVS is regulated and whether such a regulation modulates innate immune responses against RNA viruses. Through an unbiased screening by cotransfection and immunoprecipitation assays that we have previously established, 44,45 we identified OTUD4 as a MAVS-interacting DUB ( Fig. 1 and Supplementary information, Fig.…”

“…To test this hypothesis, we screened for DUBs that interact with MAVS by cotransfecting individual FLAG-tagged DUBs and HA-MAVS into HEK293 cells followed by coimmunoprecipitation and immunoblot assays. 44,45 This led to the identification of multiple DUBs that interacted with MAVS, including OTUD4, CYLD and USP35 ( Fig. 1a and Supplementary information, Fig.…”

Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA

“…Typical K48-and K63-linked ubiquitination have been extensively characterized, whereas research about other ubiquitination types remains relatively elusive. In recent years, some studies have reported that other ubiquitination types are responsible for the immunoregulation mediated by MAVS and MITA (45,46). Interestingly, an increasing number of investigations proved that there is crosstalk between the ubiquitin-proteasome and autophagy-lysosome systems, suggesting the emerging roles of ubiquitin and ubiquitin-binding proteins in selective autophagy (47,48).…”

Structure and Function of Viral Deubiquitinating Enzymes

“…Additionally, A20 can also bind to specific E2 enzymes and induce their degradation as a mechanism to prevent ubiquitination of other proteins [54]. Several more DUBs that play a role in the regulation of the immune response have been identified such as OTU DUBs Cezanne, OTULIN, and UPS DUBs USP3, 13, and 21 [7,[55][56][57][58]. Mutations in genes encoding DUBs involved in negative regulation of innate immune signaling, like CYLD and A20, can lead to the development of diseases including cancer and autoimmune and inflammatory disorders, highlighting the importance of DUB-controlled immune signaling [59,60].…”