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.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

Zhang BC,Nandakumar R,Reinert LS,Huang J,Laustsen A,Gao ZL,Sun CL,Jensen SB,Troldborg A,Assil S,Berthelsen MF,Scavenius C,Zhang Y,Windross SJ,Olagnier D,Prabakaran T,Bodda C,Narita R,Cai Y,Zhang CG,Stenmark H,Do

doi

10.1038/s41590-020-0730-5

subject

Has Abstract

pub_date

2020-08-01 00:00:00

pages

868-879

issue

8

eissn

1529-2908

issn

1529-2916

pii

10.1038/s41590-020-0730-5

journal_volume

21

pub_type

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