STEEP mediates STING ER exit and activation of signaling

Bao cun Zhang, Ramya Nandakumar, Line S. Reinert, Jinrong Huang, Anders Laustsen, Zong liang Gao, Cheng long Sun, Søren Beck Jensen, Anne Troldborg, Sonia Assil, Martin F. Berthelsen, Carsten Scavenius, Yan Zhang, Samuel J. Windross, David Olagnier, Thaneas Prabakaran, Chiranjeevi Bodda, Ryo Narita, Yujia Cai, Cong gang ZhangHarald Stenmark, Christine M. Doucet, Takeshi Noda, Zheng Guo, Raphaela Goldbach-Mansky, Rune Hartmann, Zhijian J. Chen, Jan J. Enghild, Rasmus O. Bak, Martin K. Thomsen, Søren R. Paludan

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.

Original languageEnglish (US)
Pages (from-to)868-879
Number of pages12
JournalNature immunology
Issue number8
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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