VMP1 restricts STING trafficking and activation through controlling CDIPT recruitment to ER membrane curvature.

The cGAS-STING signaling serves as a central hub for innate immunity by orchestrating type I interferon production and inflammatory cascades in response to cytosolic DNA. A critical rate-limiting step in this pathway involves STING exit from the endoplasmic reticulum (ER), a process initiated by COPII-mediated trafficking that requires ER membrane curvature formation. However, the molecular mechanism that drives this process is poorly understood. In this study, we identify VMP1, an ER-resident transmembrane protein, as a negative regulator that constrains STING ER exit and downstream signaling activation. VMP1 controlled ER PtdIns(3)P accumulation, which was essential for ER membrane curvature formation. Depletion of Vmp1 triggered CDIPT-dependent PtdIns(3)P synthesis through a non-canonical pathway independent of VPS34 stability and MTMR3 expression. Furthermore, VMP1-mediated macroautophagy degraded Rab10 GTPase, thereby suppressing CDIPT recruitment to the ER membrane. Myeloid-specific Vmp1 knockout mice exhibited augmented antiviral defense against DNA virus infection but displayed unaltered susceptibility to RNA virus infection. These results suggest that VMP1 controls STING trafficking by modulating the Rab10-CDIPT axis to restrict ER PtdIns(3)P accumulation and limit ER membrane curvature formation required for COPII vesicle biogenesis.