TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

Meixin Chen, Qingcai Meng, Yunfei Qin, Puping Liang, Peng Tan, Lian He, Yubin Zhou, Yongjun Chen, Junjiu Huang, Rong Fu Wang, Jun Cui

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14−/− mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.

Original languageEnglish (US)
Pages (from-to)105-119
Number of pages15
JournalMolecular Cell
Volume64
Issue number1
DOIs
StatePublished - Oct 6 2016

Keywords

  • TRIM14
  • USP14
  • autophagy
  • cGAS
  • p62
  • type I interferon (IFN) signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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