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

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

doi:10.1038/s41590-018-0287-8

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. Epub 2019 Jan 14.

Authors

Sonal Srikanth¹, Jin Seok Woo², Beibei Wu², Yasser M El-Sherbiny^{3

4

5}, Jennifer Leung², Koollawat Chupradit^{6

7

8}, Laura Rice⁹, Gil Ju Seo¹⁰, Guillaume Calmettes¹¹, Chandran Ramakrishna¹², Edouard Cantin¹², Dong Sung An^{6

7

8}, Ren Sun¹³, Ting-Ting Wu¹³, Jae U Jung¹⁰, Sinisa Savic^{3

14}, Yousang Gwack¹⁵

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Child, Preschool
Chlorocebus aethiops
DNA, Viral / immunology
Disease Models, Animal
Endoplasmic Reticulum / metabolism
Fibroblasts
Gene Knockout Techniques
HEK293 Cells
Herpes Simplex / immunology
Herpes Simplex / virology
Herpesvirus 1, Human / genetics
Herpesvirus 1, Human / immunology
Humans
Immunity, Innate
Interferon Type I / immunology*
Jurkat Cells
Macrophages
Male
Membrane Proteins / immunology
Membrane Proteins / metabolism*
Mice
Mice, Knockout
NIH 3T3 Cells
Neoplasm Proteins / genetics
Neoplasm Proteins / immunology
Neoplasm Proteins / metabolism*
Primary Cell Culture
Severe Combined Immunodeficiency / blood
Severe Combined Immunodeficiency / genetics
Severe Combined Immunodeficiency / immunology
Stromal Interaction Molecule 1 / genetics
Stromal Interaction Molecule 1 / immunology
Stromal Interaction Molecule 1 / metabolism*
Vero Cells

Substances

DNA, Viral
Interferon Type I
Membrane Proteins
Neoplasm Proteins
STIM1 protein, human
STING1 protein, human
Stim1 protein, mouse
Sting1 protein, mouse
Stromal Interaction Molecule 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding