@article{a5f276e8678940b894f7b15fd81d6477,
title = "STEEP mediates STING ER exit and activation of signaling",
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.",
author = "Zhang, {Bao cun} and Ramya Nandakumar and Reinert, {Line S.} and Jinrong Huang and Anders Laustsen and Gao, {Zong liang} and Sun, {Cheng long} and Jensen, {S{\o}ren Beck} and Anne Troldborg and Sonia Assil and Berthelsen, {Martin F.} and Carsten Scavenius and Yan Zhang and Windross, {Samuel J.} and David Olagnier and Thaneas Prabakaran and Chiranjeevi Bodda and Ryo Narita and Yujia Cai and Zhang, {Cong gang} and Harald Stenmark and Doucet, {Christine M.} and Takeshi Noda and Zheng Guo and Raphaela Goldbach-Mansky and Rune Hartmann and Chen, {Zhijian J.} and Enghild, {Jan J.} and Bak, {Rasmus O.} and Thomsen, {Martin K.} and Paludan, {S{\o}ren R.}",
note = "Funding Information: The technical assistance of K. S. Petersen, the AU FACS Core Facility and the AU Health Bioimaging Core Facility is greatly appreciated. We acknowledge T. Melia, Yale University, for critical reading of the manuscript. This work was funded by the European Research Council (ERC-AdG ENVISION; 786602), the Novo Nordisk Foundation (NNF18OC0030274) and the Lundbeck Foundation (R198-2015-171; R268-2016-3927); B.-c.Z. is funded by a postdoctoral grant from the Danish Council for Independent Research, Medical Sciences (5053-00083B); the postdoctoral salary to S.A. was funded by the European Union under the Horizon 2020 Research and Innovation Program and Marie Sk{\l}odowska-Curie Actions (MSCA) – international fellowship (PathAutoBio 796840); the PhD scholarship to S.J.W. was funded by the European Union under the Horizon 2020 Research and Innovation Program and the MSCA-Innovative Training Networks Programme MSCA-ITN (EDGE, 675278); the postdoctoral grant to A.T. was funded by the Lundbeck Foundation (R264-2017-3344). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = aug,
day = "1",
doi = "10.1038/s41590-020-0730-5",
language = "English (US)",
volume = "21",
pages = "868--879",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "8",
}