STEEP Mediates STING ER Exit and Activation of Signaling

Overview

Journal Nat Immunol

Date 2020 Jul 22

PMID 32690950

Citations 67

Authors

Bao-Cun Zhang

Ramya Nandakumar

Line S Reinert

Jinrong Huang

Anders Laustsen

Zong-Liang Gao

Cheng-Long Sun

Soren Beck Jensen

Anne Troldborg

Sonia Assil

Martin F Berthelsen

Carsten Scavenius

Yan Zhang

Samuel J Windross

David Olagnier

Thaneas Prabakaran

Chiranjeevi Bodda

Ryo Narita

Yujia Cai

Cong-Gang Zhang

Harald Stenmark

Christine M Doucet

Takeshi Noda

Zheng Guo

Raphaela Goldbach-Mansky

Rune Hartmann

Zhijian J Chen

Jan J Enghild

Rasmus O Bak

Martin K Thomsen

Soren R Paludan

Affiliations

Soon will be listed here.

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.

Citing Articles

A20 as a Potential Therapeutic Target for COVID-19.

Wu Y, He L, Li R, Li J, Zhao Q, Shao B Immun Inflamm Dis. 2025; 13(1):e70127.

PMID: 39853876 PMC: 11760982. DOI: 10.1002/iid3.70127.

cGAS-STING: mechanisms and therapeutic opportunities.

Zhang M, Wu C, Lu D, Wang X, Shang G Sci China Life Sci. 2025; .

PMID: 39821837 DOI: 10.1007/s11427-024-2808-3.

Regulation of cGAS-STING signalling and its diversity of cellular outcomes.

Zhang Z, Zhang C Nat Rev Immunol. 2025; .

PMID: 39774812 DOI: 10.1038/s41577-024-01112-7.

The cGAS-STING pathway in ischemia-reperfusion injury in acute cerebral infarction: a new therapeutic opportunities?.

Hu J, Tian M Front Neurol. 2025; 15:1471287.

PMID: 39741707 PMC: 11685085. DOI: 10.3389/fneur.2024.1471287.

Emerging concepts and treatments in autoinflammatory interferonopathies and monogenic systemic lupus erythematosus.

Goldbach-Mansky R, Alehashemi S, de Jesus A Nat Rev Rheumatol. 2024; 21(1):22-45.

PMID: 39623155 DOI: 10.1038/s41584-024-01184-8.

References

Paludan S . Activation and regulation of DNA-driven immune responses. Microbiol Mol Biol Rev. 2015; 79(2):225-41. PMC: 4429241. DOI: 10.1128/MMBR.00061-14. View

Sun L, Wu J, Du F, Chen X, Chen Z . Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2012; 339(6121):786-91. PMC: 3863629. DOI: 10.1126/science.1232458. View

Wu J, Sun L, Chen X, Du F, Shi H, Chen C . Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science. 2012; 339(6121):826-30. PMC: 3855410. DOI: 10.1126/science.1229963. View

Ishikawa H, Barber G . STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008; 455(7213):674-8. PMC: 2804933. DOI: 10.1038/nature07317. View

Shang G, Zhang C, Chen Z, Bai X, Zhang X . Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. Nature. 2019; 567(7748):389-393. PMC: 6859894. DOI: 10.1038/s41586-019-0998-5. View

Tanaka Y, Chen Z . STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal. 2012; 5(214):ra20. PMC: 3549669. DOI: 10.1126/scisignal.2002521. View

Liu S, Cai X, Wu J, Cong Q, Chen X, Li T . Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015; 347(6227):aaa2630. DOI: 10.1126/science.aaa2630. View

Prabakaran T, Bodda C, Krapp C, Zhang B, Christensen M, Sun C . Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO J. 2018; 37(8). PMC: 5897779. DOI: 10.15252/embj.201797858. View

Gulen M, Koch U, Haag S, Schuler F, Apetoh L, Villunger A . Signalling strength determines proapoptotic functions of STING. Nat Commun. 2017; 8(1):427. PMC: 5585373. DOI: 10.1038/s41467-017-00573-w. View

10.

Reinert L, Lopusna K, Winther H, Sun C, Thomsen M, Nandakumar R . Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS. Nat Commun. 2016; 7:13348. PMC: 5109551. DOI: 10.1038/ncomms13348. View

11.

Li X, Wu J, Gao D, Wang H, Sun L, Chen Z . Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science. 2013; 341(6152):1390-4. PMC: 3863637. DOI: 10.1126/science.1244040. View

12.

Woo S, Fuertes M, Corrales L, Spranger S, Furdyna M, Leung M . STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014; 41(5):830-42. PMC: 4384884. DOI: 10.1016/j.immuni.2014.10.017. View

13.

Crow Y, Hayward B, Parmar R, Robins P, Leitch A, Ali M . Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet. 2006; 38(8):917-20. DOI: 10.1038/ng1845. View

14.

Liu Y, Jesus A, Marrero B, Yang D, Ramsey S, Sanchez G . Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014; 371(6):507-518. PMC: 4174543. DOI: 10.1056/NEJMoa1312625. View

15.

Hanson M, Crespo M, Abraham W, Moynihan K, Szeto G, Chen S . Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants. J Clin Invest. 2015; 125(6):2532-46. PMC: 4497758. DOI: 10.1172/JCI79915. View

16.

Haag S, Gulen M, Reymond L, Gibelin A, Abrami L, Decout A . Targeting STING with covalent small-molecule inhibitors. Nature. 2018; 559(7713):269-273. DOI: 10.1038/s41586-018-0287-8. View

17.

Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H . Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A. 2009; 106(49):20842-6. PMC: 2791563. DOI: 10.1073/pnas.0911267106. View

18.

Dobbs N, Burnaevskiy N, Chen D, Gonugunta V, Alto N, Yan N . STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease. Cell Host Microbe. 2015; 18(2):157-68. PMC: 4537353. DOI: 10.1016/j.chom.2015.07.001. View

19.

Srikanth S, Woo J, Wu B, El-Sherbiny Y, Leung J, Chupradit K . The Ca sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat Immunol. 2019; 20(2):152-162. PMC: 6340781. DOI: 10.1038/s41590-018-0287-8. View

20.

Konno H, Konno K, Barber G . Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell. 2013; 155(3):688-98. PMC: 3881181. DOI: 10.1016/j.cell.2013.09.049. View