title: STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease.
abstract: STING is an ER-associated membrane protein that is critical for innate immune sensing of pathogens. STING-mediated activation of the IFN-I pathway through the TBK1/IRF3 signaling axis involves both cyclic-dinucleotide binding and its translocation from the ER to vesicles. However, how these events are coordinated, and the exact mechanism of STING activation, remain poorly understood. Here, we found that the Shigella effector protein IpaJ potently inhibits STING signaling by blocking its translocation from the ER to ERGIC, even in the context of dinucleotide binding. Reconstitution using purified components revealed STING translocation as the rate-limiting event in maximal signal transduction. Furthermore, STING mutations associated with autoimmunity in humans were found to cause constitutive ER exit and to activate STING independent of cGAMP binding. Together, these data provide compelling evidence for an ER retention and ERGIC/Golgi-trafficking mechanism of STING regulation that is subverted by bacterial pathogens and is deregulated in human genetic disease.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Dobbs
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Burnaevskiy
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Didi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Gonugunta
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: neal.alto@utsouthwestern.edu.
authors.forename: Neal M
authors.initials: NM
authors.lastname: Alto
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: nan.yan@utsouthwestern.edu.
authors.forename: Nan
authors.initials: N
authors.lastname: Yan
mesh_terms: D000818:Animals; D002460:Cell Line; D054884:Host-Pathogen Interactions; D007370:Interferon Type I / Q000096:biosynthesis; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D021381:Protein Transport; D012760:Shigella / Q000276:immunology* / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation; D000099197:STING Protein
chemical_list: D007370:Interferon Type I; D008565:Membrane Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein