MINT3 promotes STING activation and facilitates antiviral immune responses

Abstract

Stimulator-of-interferon genes (STING) translocation is the rate-limiting step in the cGAS-STING signaling which detects cytosolic DNA and produces type I interferons. However, the mechanism by which this process is modulated remains to be further clarified. In the present study, we identified munc18–1-interacting protein 3 (MINT3) as a positive regulator of STING signaling. MINT3 promotes type I interferons production induced by herpes simplex virus-1 (HSV-1) infection and ISD or cGAMP stimulation in mouse peritoneal macrophages. Deficiency of Mint3 greatly inhibited STING and IRF3 activation in macrophages. Mint3 knockdown also attenuated STING and IRF3 activation in macrophages, human THP-1 cells, and RAW264.7 cells. Mechanistically, MINT3 interacted with STING, selectively enhanced its K63-linked polyubiquitination and facilitated STING translocation to the Golgi, resulting in the enhancement of the STING and TBK1 interaction. Furthermore, MINT3 also facilitated HSV-1-induced innate antiviral immune responses and impaired HSV-1 replication in vitro and in vivo. Interestingly, we showed that the expression of MINT3 was dramatically elevated during HSV-1 infection, and ISD stimulation in macrophages. Thus, we have revealed a feedback mechanism for the regulation of the cGAS-STING pathway, providing a promising therapeutic target for the treatment of disorders triggered by aberrant STING activity.