STEEP mediates STING ER exit and activation of signaling

Bao-Cun Zhang (1) , Ramya Nandakumar (1) , Line Reinert (1) , Anders Laustsen (1) , Søren Beck Jensen (1) , Sonia Assil (1) , Martin F. Bertehlsen (1, 2) , Carsten Scavenius (2, 2) , Samuel J. Windross (1) , Chenglong Sun (1) , Chiranjeevi Bodda (1) , Ryo Narita (1, 2) , Yujia Cai (1) , Harald Stenmark (3) , Christine M Doucet (4) , Takeshi Noda (5) , Raphaela Goldbach-Mansky (6) , Rune Hartmann (2) , Jan J. Enghild (2, 2) , Rasmus O. Bak (1) , Martin K. Thomsen (1) , Søren R. Paludan (1, 2)

1 Department of Biomedicine Aarhus
2 Aarhus University [Aarhus]
3 Institute for Cancer Research [Oslo]
4 CBS - Centre de Biochimie Structurale [Montpellier]
5 Graduate School of Frontier Biosciences [Osaka]
6 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]

STING is essential for control of infections and for tumor immunosurveillance, but can also drive pathological inflammation. STING resides on the ER, and traffics following stimulation to 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 STING traffic from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PI3P) production, which promotes ER membrane curvature formation and facilitates COPII-mediated ER-Golgi traffic of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from SAVI patients. Interestingly, SAVI-associated STING mutants interacted strongly with STEEP leading to increased ER PI3P levels and membrane curvature. Thus, STEEP promotes STING signaling by allowing ER exit.

Mots clés: Innate immunology; DNA sensing; cGAS-STING pathway; Intracellular trafficking; SAVI

Domaines: Sciences du Vivant [q-bio]

Bao-Cun Zhang, Ramya Nandakumar, Line Reinert, Anders Laustsen, Søren Beck Jensen, et al.. STEEP mediates STING ER exit and activation of signaling. Nature Immunology, 2020, 21 (8), pp.868-879. ⟨10.1038/s41590-020-0730-5⟩. ⟨hal-03103929⟩