内质网
刺
刺激1
细胞生物学
干扰素基因刺激剂
干扰素
高尔基体
信号转导
生物
免疫学
先天免疫系统
免疫系统
工程类
航空航天工程
作者
Sonal Srikanth,Jin Seok Woo,Beibei Wu,Yasser M. El‐Sherbiny,Jennifer Leung,Koollawat Chupradit,Laura Rice,Gil Ju Seo,Guillaume Calmettes,Chandran Ramakrishna,Edouard M. Cantin,Dong Sung An,Ren Sun,Ting-Ting Wu,Jae U. Jung,Sinisa Savic,Yousang Gwack
标识
DOI:10.1038/s41590-018-0287-8
摘要
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 Ca2+ 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. STIM1 is a calcium sensor that is essential for functional lymphocyte responses. Gwack and colleagues demonstrate a calcium-independent role for STIM1 in macrophages that regulates their production of type I interferons.
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