The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum

Srikanth, S., Woo, J.S., Wu, B., El-Sherbiny, Y.M. ORCID: 0000-0003-4791-3475, Leung, J., Chupradit, K., Rice, L., Seo, G.J., Calmettes, G., Ramakrishna, C., Cantin, E., An, D.S., Sun, R., Wu, T.-T., Jung, J.U., Savic, S. and Gwack, Y., 2019. The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nature Immunology, 20 (2), pp. 152-162. ISSN 1529-2908

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Abstract

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+ 36 sensor STIM1 caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient suffering from combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and co-expression of full-length 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.

Item Type: Journal article
Publication Title: Nature Immunology
Creators: Srikanth, S., Woo, J.S., Wu, B., El-Sherbiny, Y.M., Leung, J., Chupradit, K., Rice, L., Seo, G.J., Calmettes, G., Ramakrishna, C., Cantin, E., An, D.S., Sun, R., Wu, T.-T., Jung, J.U., Savic, S. and Gwack, Y.
Publisher: Nature Publishing Group
Date: February 2019
Volume: 20
Number: 2
ISSN: 1529-2908
Identifiers:
NumberType
10.1038/s41590-018-0287-8DOI
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 21 Dec 2018 11:30
Last Modified: 14 Jul 2019 03:00
URI: http://irep.ntu.ac.uk/id/eprint/35416

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