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

  • Author(s): Srikanth, Sonal
  • Woo, Jin Seok
  • Wu, Beibei
  • El-Sherbiny, Yasser M
  • Leung, Jennifer
  • Chupradit, Koollawat
  • Rice, Laura
  • Seo, Gil Ju
  • Calmettes, Guillaume
  • Ramakrishna, Chandran
  • Cantin, Edouard
  • An, Dong Sung
  • Sun, Ren
  • Wu, Ting-Ting
  • Jung, Jae U
  • Savic, Sinisa
  • Gwack, Yousang
  • et al.
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.

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