EXOC5/SEC10 attenuates antiviral IFN-I signaling by targeting STING1 for autophagic degradation.

EXOC5/SEC10, the central subunit of the exocyst complex, is crucial for the trafficking of secretory vesicles to the plasma membrane. However, its role in innate immunity and viral replication remains unclear. Here we demonstrate that EXOC5 acts as a negative regulator of DNA virus-triggered CGAS-STING1 signaling via targeting STING1. Mechanistically, EXOC5 facilitates the autophagic degradation of STING1 via K63-linked polyubiquitination at Lys224 and Lys338 by the E3 ligase TRIM56, which serves as a recognition signal for the cargo receptor SQSTM1/p62 (sequestosome 1). Furthermore, EXOC5 inhibits antiviral innate immunity and promotes viral replication via EXOC5-TRIM56-STING1-SQSTM1 signal transduction. More importantly, myeloid-specific deletion of Exoc5 in mice improves survival and reduces viral load. In general, these findings revealed a negative feedback loop of type I interferon signaling through the EXOC5-TRIM56-STING1-SQSTM1 axis, which has the potential to serve as a new target for the development of antiviral therapeutics that regulate the host immune response.Abbreviations: BafA1: bafilomycin A1; BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; EXOC5/SEC10: exocyst complex component 5; HAdV-4: human adenovirus type 4; HSV-1: herpes simplex virus type 1; HT-DNA: herring testis deoxyribonucleic acid; IFN: interferon; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; PMs: peritoneal macrophages; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; VACV70: 70-mers of dsDNA representing the genome of vaccinia virus.