STEEP mediates STING ER exit and activation of signaling.

Nature Immunology
Bao-Cun ZhangSoren R. Paludan

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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Citations

Sep 30, 2020·The Journal of Experimental Medicine·Sophie Rivara, Andrea Ablasser
Nov 26, 2020·The FEBS Journal·Katherine R Balka, Dominic De Nardo
Jan 20, 2021·Trends in Biochemical Sciences·Nimi Vashi, Samuel F Bakhoum
Feb 26, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Shan-Shan ZouJingtao Chen
Feb 27, 2021·Frontiers in Immunology·Haruna OkudeTaro Kawai
Apr 10, 2021·Nature Reviews. Immunology·Alexiane DecoutAndrea Ablasser
Jun 4, 2021·Signal Transduction and Targeted Therapy·Ruoxi ZhangDaolin Tang
May 21, 2021·Frontiers in Immunology·Tomohiko TaguchiRuri Shindo
Jun 5, 2021·Frontiers in Immunology·Roberto AmadioFederica Benvenuti

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
co-immunoprecipitation
PCR
immunoprecipitation
electrophoresis
confocal microscopy
ELISA
GTPase
PMA
ICE
Assay

Software Mentioned

DESeq2
Zen Blue
R
STING
STEEP
Mascot
ImageStream
IDEAS

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