ISGylation by HERCs facilitates STING activation
Cell Reports(2024)
摘要
Optimal activation of stimulator of interferon genes (STING) protein is crucial for host defenses against pathogens and avoiding detrimental effects. Various post-translational modifications control STING activity. However, the function of interferon (IFN)-stimulated gene (ISG) 15 modification (ISGylation) in controlling STING stability and activation is unclear. Here, we show that the E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice) facilitate STING activation by mediating ISGylation of STING at K150, preventing its K48-linked ubiquitination and degradation. Concordantly, Herc6 deficiency suppresses herpes simplex virus 1 infection-induced type I IFN responses and facilitates viral replication both in vitro and in vivo. Notably, severe acute respiratory syndrome coronavirus 2 protein papain-like protease cleaves HERC5-mediated ISGylation of STING, suppressing host antiviral responses. These data identify a mechanism by which HERCs-mediated ISGylation controls STING stability and activation and uncover the correlations and interactions of ISGylation and ubiquitination during STING activation.
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关键词
STING,HERCs,ISGylation,post-translational modifications,SARS-CoV-2 protein PLpro,Antiviral innate immunity
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