Srikanth, S, Woo, JS, Wu, B et al. (14 more authors) (2019) The Ca²⁺ sensor STIM1 regulates type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nature Immunology. pp. 152-162. ISSN 1529-2908
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s), under exclusive licence to Springer Nature Limited 2019. This is a post-peer-review, pre-copyedit version of an article published in Nature Immunology. The final authenticated version is available online at: https://doi.org/10.1038/s41590-018-0287-8. |
Keywords: | Innate immunity; Signal transduction |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Experimental Musculoskeletal Medicine (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 02 Jan 2019 13:51 |
Last Modified: | 14 Jul 2019 00:43 |
Status: | Published |
Publisher: | Nature Publishing Group |
Identification Number: | 10.1038/s41590-018-0287-8 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:140349 |