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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