STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the 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 trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.

STING 对控制感染和肿瘤免疫监测至关重要，但它也可以引发病理性炎症。STING 驻留在内质网 (ER) 上，并在刺激到发生信号的 ERGIC/高尔基体后运输。尽管 STING ER 退出是 STING 信号中的限速步骤，但驱动此过程的机制尚不清楚。在这里，我们将 STEEP 确定为 STING 信号的正调节器。STEEP 与 STING 有关联，并促进了 ER 的贩运。这是通过刺激 3-磷酸磷脂酰肌醇 (PtdIns(3)P) 产生和 ER 膜曲率形成来介导的，从而诱导 COPII 介导的 STING ER 到高尔基体的运输。STEEP 的消耗损害了 STING 驱动的基因表达，以响应脑组织和 STING 相关疾病患者细胞中的病毒感染。有趣的是，来自患者的 STING 功能获得突变体与 STEEP 相互作用强烈，导致 ER PtdIns(3)P 水平和膜曲率增加。因此，STEEP 通过促进 ER 退出来启用 STING 信号。