期刊
NATURE IMMUNOLOGY
卷 20, 期 2, 页码 152-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-018-0287-8
关键词
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类别
资金
- National Institutes of Health [AI083432, DE028432, AI130653]
- Fletcher Jones Foundation
- Whittier Foundation
- [CA180779]
- [CA200422]
- [AI073099]
- [AI116585]
- [AI129496]
- [AI140705]
- [DE023926]
- [DE027888]
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.
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