Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Biology, University of Copenhagen , Copenhagen, Denmark.
Nat Immunol. 2020 Aug;21(8):868-879. doi: 10.1038/s41590-020-0730-5. Epub 2020 Jul 20.
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 对于控制感染和肿瘤免疫监视至关重要,但它也可能引发病理性炎症。STING 位于内质网 (ER) 上,并在受到 ERGIC/Golgi 的刺激后进行运输,信号在此处发生。尽管 STING ER 出口是 STING 信号转导的限速步骤,但驱动这一过程的机制尚不清楚。在这里,我们鉴定出 STEEP 是 STING 信号转导的正向调节剂。STEEP 与 STING 相关,并促进其从 ER 运输。这是通过刺激磷脂酰肌醇-3-磷酸 (PtdIns(3)P) 的产生和 ER 膜曲率的形成来介导的,从而诱导 COPII 介导的 STING 的 ER 到高尔基体的运输。STEEP 的耗竭会损害病毒感染脑组织和 STING 相关疾病患者细胞中 STING 驱动的基因表达。有趣的是,来自患者的 STING 功能获得性突变与 STEEP 强烈相互作用,导致 ER PtdIns(3)P 水平和膜曲率增加。因此,STEEP 通过促进 ER 出口来实现 STING 信号转导。