STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production.
?-interferon-inducible protein-16 (IFI16), a key DNA sensor, triggers downstream STING-dependent type I interferon (IFN-I) production and antiviral immunity. 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 the E3 ligase TRIM21. The 1-pyrin region of IFI16 is responsible for the IFI16-STING interaction, and the first three lysines in the N-terminal region of IFI16 are the key sites that lead to STING-mediated IFI16 ubiquitination and degradation. Compared to wild-type IFI16, a higher level of viral DNA triggered IFN-? and antiviral IFN-stimulated gene expression, and thus less HSV-1 infection, was observed in the cells transfected with IFI16-K3/4/6R, an IFI16 mutant that is resistant to degradation. STING-mediated negative feedback regulation of IFI16 restricts IFN-I overproduction during antiviral immunity to avoid autoimmune diseases.
Mesh Terms:
Cell Line, Humans, Interferon-beta, Lysine, Membrane Proteins, Models, Biological, Nuclear Proteins, Phosphoproteins, Proteasome Endopeptidase Complex, Protein Domains, Protein Stability, Proteolysis, Ribonucleoproteins, Signal Transduction, Structure-Activity Relationship, Ubiquitin, Ubiquitination
Cell Line, Humans, Interferon-beta, Lysine, Membrane Proteins, Models, Biological, Nuclear Proteins, Phosphoproteins, Proteasome Endopeptidase Complex, Protein Domains, Protein Stability, Proteolysis, Ribonucleoproteins, Signal Transduction, Structure-Activity Relationship, Ubiquitin, Ubiquitination
Cell Rep
Date: Dec. 29, 2018
PubMed ID: 31665637
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