STEEP mediates STING ER exit and activation of signaling

Nat Immunol. 2020 Aug;21(8):868-879. doi: 10.1038/s41590-020-0730-5.

Bao-Cun Zhang ¹, Ramya Nandakumar ^# ¹, Line S Reinert ^# ¹, Jinrong Huang ¹ ², Anders Laustsen ¹, Zong-Liang Gao ¹, Cheng-Long Sun ¹, Søren Beck Jensen ¹, Anne Troldborg ¹ ³ ⁴, Sonia Assil ¹, Martin F Berthelsen ¹ ³, Carsten Scavenius ⁵, Yan Zhang ⁶, Samuel J Windross ¹, David Olagnier ¹, Thaneas Prabakaran ¹, Chiranjeevi Bodda ¹, Ryo Narita ¹ ⁵, Yujia Cai ¹, Cong-Gang Zhang ⁷ ⁸, Harald Stenmark ⁹, Christine M Doucet ¹⁰, Takeshi Noda ¹¹, Zheng Guo ⁶, Raphaela Goldbach-Mansky ¹², Rune Hartmann ⁵, Zhijian J Chen ⁷ ⁸, Jan J Enghild ⁵, Rasmus O Bak ¹ ¹³, Martin K Thomsen ¹ ³, Søren R Paludan ¹⁴

Affiliations

1 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
2 Department of Biology, University of Copenhagen , Copenhagen, Denmark.
3 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
4 Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.
5 Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
6 Department of Engineering, Aarhus University, Aarhus, Denmark.
7 Department of Molecular Biology, Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
8 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
9 Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
10 Centre de Biochimie Structurale (CBS), INSERM, CNRS, Université de Montpellier, Montpellier, France.
11 Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
12 Translational Autoinflammatory Diseases Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
13 Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark.
14 Department of Biomedicine, Aarhus University, Aarhus, Denmark. srp@biomed.au.dk.
# Contributed equally.

PMID: 32690950 DOI: 10.1038/s41590-020-0730-5

Abstract

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.

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