Abstract
STING is essential for control of infections and for tumor immunosurveillance, but can also drive pathological inflammation. STING resides on the ER, and traffics following stimulation to ERGIC/Golgi where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted STING traffic from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PI3P) production, which promotes ER membrane curvature formation and facilitates COPII-mediated ER-Golgi traffic of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from SAVI patients. Interestingly, SAVI-associated STING mutants interacted strongly with STEEP leading to increased ER PI3P levels and membrane curvature. Thus, STEEP promotes STING signaling by allowing ER exit.