TENT5A anchors STING at the endoplasmic reticulum to block SEC24B-dependent trafficking and suppress cGAS-STING signaling

Abstract

The cGAS-STING pathway is a central sensor of cytosolic DNA that drives type I interferon responses during infection and tumor surveillance. Activation of STING requires coordinated trafficking from the endoplasmic reticulum (ER) to the Golgi, yet how this spatial transition is regulated by ER-resident factors remains incompletely understood. Here we identify TENT5A as an ER-localized negative regulator of STING signaling. Genetic depletion of TENT5A markedly enhances cGAS-STING-dependent type I interferon production in response to cytosolic DNA and DNA virus infection. Conversely, TENT5A overexpression suppresses downstream signaling and antiviral gene expression. Mechanistically, TENT5A directly interacts with the C-terminal tail of STING and competes with the COPII adaptor SEC24B, thereby preventing STING incorporation into COPII vesicles and blocking its ER-to-Golgi trafficking. This ER retention inhibits STING oligomerization, TBK1 recruitment and IRF3 activation, ultimately attenuating type I interferon responses. In vivo, myeloid-specific deletion of TENT5A enhances systemic interferon responses, restricts herpesvirus replication, and improves host survival. Moreover, TENT5A deficiency promotes CD8 T cell effector activation within the tumor microenvironment and suppresses tumor growth in a melanoma model. Together, our findings define TENT5A as an ER checkpoint that spatially controls STING trafficking through competition with COPII machinery, revealing vesicular sorting as a regulatory layer of innate immune activation.