STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production and P53-Dependent Apoptosis
72 Pages Posted: 4 Feb 2019 Sneak Peek Status: PublishedMore...
Gamma-interferon-inducible protein-16 (IFI16), a key DNA sensor, triggers downstream STING-dependent type I interferon (IFN-I) production and p53-dependent apoptosis. However, it is still unclear how to negatively regulate IFI16 to avoid excessive IFN-I production and autoimmunity. Here we find that STING directly interacts with IFI16 and facilitates IFI16 degradation via the ubiquitin-proteasome pathway by recruiting E3 ligase TRIM21. We have also identified the key sites which lead to STING-mediated IFI16 ubiquitination and degradation. Comparing to IFI16-WT, higher level of viral DNA-triggered IFN-β was detected in the cells transfected with IFI16-K3/4/6R, an IFI16 mutant resistant to degradation. In addition, overexpression of STING significantly reduces Ser392-phosphorylated p53 and apoptosis in WT U2OS cells rather than in IFI16-/- cells, suggesting that STING-mediated IFI16 degradation suppresses p53-dependent apoptosis, and thus may promote DNA virus-induced tumorigenesis. Our study has described that STING-mediated negative feedback regulation of IFI16 controls both IFN-I production and p53-dependent apoptosis.
Keywords: IFI16, STING, TIRM21, ubiquitin proteasome system, type I interferon, antiviral immunity, p53, apoptosis, tumorigenesis
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