Department of Physiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
National Institute for Health Research-Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, UK.
Nat Immunol. 2019 Feb;20(2):152-162. doi: 10.1038/s41590-018-0287-8. Epub 2019 Jan 14.
Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.
干扰素基因刺激蛋白 (STING) 是内质网 (ER) 信号接头蛋白，对于 DNA 病原体的 I 型干扰素反应至关重要。STING 的异常激活与自身免疫和自身炎症性疾病的病理学有关。STING 激活的限速步骤是其从内质网向 ER-Golgi 中间隔室的易位。在这里，我们发现钙传感器基质相互作用分子 1 (STIM1) 的缺乏导致 STING 在静止状态下自发激活，并增强了小鼠和一名联合免疫缺陷患者的 I 型干扰素的表达。从机制上讲，STIM1 与 STING 结合，将其保留在 ER 膜上，全长 STIM1 或 STIM1 的 STING 相互作用片段的共表达抑制了导致自身炎症性疾病的显性 STING 突变体的功能。此外，STIM1 的缺乏强烈增强了病毒感染后 I 型干扰素的表达，并防止了体内 DNA 病毒感染的致死性。这项工作描绘了一个 STIM1-STING 回路，该回路维持了 STING 途径的静止状态。
