The Ca 2+ 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.

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