1. The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum
- Author
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Srikanth, Sonal, Woo, Jin Seok, Wu, Beibei, El-Sherbiny, Yasser M, Leung, Jennifer, Chupradit, Koollawat, Rice, Laura, Seo, Gil Ju, Calmettes, Guillaume, Ramakrishna, Chandran, Cantin, Edouard, An, Dong Sung, Sun, Ren, Wu, Ting-Ting, Jung, Jae U, Savic, Sinisa, and Gwack, Yousang
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Vaccine Related ,Prevention ,Biodefense ,Emerging Infectious Diseases ,Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Child ,Preschool ,Chlorocebus aethiops ,DNA ,Viral ,Disease Models ,Animal ,Endoplasmic Reticulum ,Fibroblasts ,Gene Knockout Techniques ,HEK293 Cells ,Herpes Simplex ,Herpesvirus 1 ,Human ,Humans ,Immunity ,Innate ,Interferon Type I ,Jurkat Cells ,Macrophages ,Male ,Membrane Proteins ,Mice ,Mice ,Knockout ,NIH 3T3 Cells ,Neoplasm Proteins ,Primary Cell Culture ,Severe Combined Immunodeficiency ,Stromal Interaction Molecule 1 ,Vero Cells ,Immunology ,Biochemistry and cell biology - Abstract
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.
- Published
- 2019