USP13 negatively regulates antiviral responses by deubiquitinating STING

He Sun et al. Nat. Commun. (2017) 8:15534.

Abstract

To trigger type I interferon and proinflammatory cytokine production in response to DNA virus infection, stimulator of interferon genes (STING) recruits and activates critical signaling molecules including TANK-binding kinase 1 (TBK1).¹ As the functions and expression of STING is regulated by posttranslational modifications such as ubiquitination, STING has been found as a target of various ubiquitin ligases.^2,3 However, the deubiquitinases (DUBs) for STING regulation remain unknown. In this study, the authors screened a superfamily of DUBs and found that ubiquitin-specific protease 13 (USP13) can interact with STING and negatively regulate IFN-β promoter activity in HEK293 transfection system. Knockdown or knockout of USP13 resulted in a higher expression level of interferon and proinflammatory cytokines upon herpes simplex virus 1 infection in vitro and in vivo, indicating that USP13 serves as a negative regulator therein. In addition, the authors revealed that deubiquitinase activity of USP13 is required to remove K27-linked polyubiquitination from STING, thus inhibiting TBK1 recruitment and activation of downstream transcription factors. This study not only uncovers a previously uncharacterized role of USP13 in reduction of antiviral inflammation but also suggests USP13 as a potential target for medically modulating innate immune responses.

References

1.          Takayuki Abe et al. Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-B Activation through TBK1. J Virol. (2014) 88: 5328 –5341.

2.          Bo Zhong et al. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. Immunity (2009) 30:397–407.

3.          Qiang Wang et al. The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. Immunity (2014) 41:919–933.