The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum PMID: 30643259

RQC and Longevity Regulation

2026-09-03

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

Nat Immunol. 2019 Feb;20(2):152-162. doi: 10.1038/s41590-018-0287-8.

Sonal Srikanth ¹ , Jin Seok Woo ² , Beibei Wu ² , Yasser M El-Sherbiny ³ ⁴ ⁵ , Jennifer Leung ² , Koollawat Chupradit ⁶ ⁷ ⁸ , Laura Rice ⁹ , Gil Ju Seo ¹⁰ , Guillaume Calmettes ¹¹ , Chandran Ramakrishna ¹² , Edouard Cantin ¹² , Dong Sung An ⁶ ⁷ ⁸ , Ren Sun ¹³ , Ting-Ting Wu ¹³ , Jae U Jung ¹⁰ , Sinisa Savic ³ ¹⁴ , Yousang Gwack ¹⁵

Affiliations

1. Department of Physiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. [email protected].
2. Department of Physiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
3. National Institute for Health Research-Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, UK.
4. Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
5. School of Science and Technology, Department of Biosciences, Nottingham Trent University, Nottingham, UK.
6. Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
7. School of Nursing, University of California at Los Angeles, Los Angeles, CA, USA.
8. UCLA AIDS Institute, Los Angeles, CA, USA.
9. Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, UK.
10. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
11. Department of Medicine (Cardiology), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
12. Department of Molecular Immunology, City of Hope Beckman Research Institute, Duarte, CA, USA.
13. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
14. Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, UK.
15. Department of Physiology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. [email protected].

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.