The Ca Sensor STIM1 Regulates the Type I Interferon Response by Retaining the Signaling Adaptor STING at the Endoplasmic Reticulum

Overview

Journal Nat Immunol

Date 2019 Jan 16

PMID 30643259

Citations 170

Authors

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 Cantin

Dong Sung An

Ren Sun

Ting-Ting Wu

Jae U Jung

Sinisa Savic

Yousang Gwack

Affiliations

Soon will be listed here.

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 Ca 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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