{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:23:02Z","timestamp":1790774582814,"version":"4.1.0"},"reference-count":37,"publisher":"Rockefeller University Press","issue":"11","license":[{"start":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T00:00:00Z","timestamp":1595894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T00:00:00Z","timestamp":1620000000000},"content-version":"vor","delay-in-days":279,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008069","name":"UCSF","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007100","name":"Sandler Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007100","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01AI137249"],"award-info":[{"award-number":["R01AI137249"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01HL122533"],"award-info":[{"award-number":["R01HL122533"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R00HL135403"],"award-info":[{"award-number":["R00HL135403"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["PO1HL103453"],"award-info":[{"award-number":["PO1HL103453"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP19H00974"],"award-info":[{"award-number":["JP19H00974"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP15H05903"],"award-info":[{"award-number":["JP15H05903"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP17K15445"],"award-info":[{"award-number":["JP17K15445"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20H03202"],"award-info":[{"award-number":["JP20H03202"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AMED-PRIME","award":["17939604"],"award-info":[{"award-number":["17939604"]}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,11,2]]},"abstract":"<jats:p>Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi\u2013ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon\u2013driven inflammation in CopaE241K\/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.<\/jats:p>","DOI":"10.1084\/jem.20201045","type":"journal-article","created":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T02:21:48Z","timestamp":1594261308000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":206,"title":["A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8956-0199","authenticated-orcid":true,"given":"Zimu","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6195-3452","authenticated-orcid":true,"given":"Zhenlu","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher S.","family":"Law","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9806-910X","authenticated-orcid":true,"given":"Kojiro","family":"Mukai","sequence":"additional","affiliation":[{"name":"Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances O.","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tereza","family":"Martinu","sequence":"additional","affiliation":[{"name":"Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley J.","family":"Backes","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter L.","family":"Eckalbar","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0464-6370","authenticated-orcid":true,"given":"Tomohiko","family":"Taguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5139-4802","authenticated-orcid":true,"given":"Anthony K.","family":"Shum","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, San Francisco, CA 1"},{"name":"Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 4"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2020,7,28]]},"reference":[{"key":"2023072622175062000_bib1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41590-019-0556-1","article-title":"Regulation of cGAS- and RLR-mediated immunity to nucleic acids","volume":"21","author":"Ablasser","year":"2020","journal-title":"Nat. Immunol"},{"key":"2023072622175062000_bib2","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.celrep.2018.12.041","article-title":"Proteomic Profiling of Mammalian COPII and COPI Vesicles","volume":"26","author":"Adolf","year":"2019","journal-title":"Cell Rep"},{"key":"2023072622175062000_bib3","doi-asserted-by":"publisher","first-page":"2360","DOI":"10.4049\/jimmunol.2000028","article-title":"A Defect in Thymic Tolerance Causes T Cell-Mediated Autoimmunity in a Murine Model of COPA Syndrome","volume":"204","author":"Deng","year":"2020","journal-title":"J. Immunol"},{"key":"2023072622175062000_bib4","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.chom.2015.07.001","article-title":"STING Activation by Translocation from the ER Is Associated with Infection and Autoinflammatory Disease","volume":"18","author":"Dobbs","year":"2015","journal-title":"Cell Host Microbe"},{"key":"2023072622175062000_bib5","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"2023072622175062000_bib6","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.908","article-title":"Isolation of Mouse Embryo Fibroblasts","volume":"3","author":"Durkin","year":"2013","journal-title":"Bio Protoc"},{"key":"2023072622175062000_bib7","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.38839","article-title":"The cargo receptor SURF4 promotes the efficient cellular secretion of PCSK9","volume":"7","author":"Emmer","year":"2018","journal-title":"eLife"},{"key":"2023072622175062000_bib8","doi-asserted-by":"publisher","first-page":"3905","DOI":"10.1093\/emboj\/19.15.3905","article-title":"COP I domains required for coatomer integrity, and novel interactions with ARF and ARF-GAP","volume":"19","author":"Eugster","year":"2000","journal-title":"EMBO J"},{"key":"2023072622175062000_bib9","doi-asserted-by":"publisher","first-page":"2810","DOI":"10.1093\/bioinformatics\/btt487","article-title":"RDAVIDWebService: a versatile R interface to DAVID","volume":"29","author":"Fresno","year":"2013","journal-title":"Bioinformatics"},{"key":"2023072622175062000_bib10","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/s41586-019-1006-9","article-title":"Autophagy induction via STING trafficking is a primordial function of the cGAS pathway","volume":"567","author":"Gui","year":"2019","journal-title":"Nature"},{"key":"2023072622175062000_bib11","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/s41586-018-0287-8","article-title":"Targeting STING with covalent small-molecule inhibitors","volume":"559","author":"Haag","year":"2018","journal-title":"Nature"},{"key":"2023072622175062000_bib12","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1128\/MCB.22.7.2111-2123.2002","article-title":"Enumeration of the simian virus 40 early region elements necessary for human cell transformation","volume":"22","author":"Hahn","year":"2002","journal-title":"Mol. Cell. Biol"},{"key":"2023072622175062000_bib13","doi-asserted-by":"publisher","first-page":"R183","DOI":"10.1186\/gb-2007-8-9-r183","article-title":"The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists","volume":"8","author":"Huang","year":"2007","journal-title":"Genome Biol"},{"key":"2023072622175062000_bib14","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/nature22366","article-title":"Architecture of the human interactome defines protein communities and disease networks","volume":"545","author":"Huttlin","year":"2017","journal-title":"Nature"},{"key":"2023072622175062000_bib15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.5152\/eurjrheum.2019.18177","article-title":"Baricitinib in therapy of COPA syndrome in a 15-year-old girl","volume":"1\u20134","author":"Krutzke","year":"2019","journal-title":"Eur. J. Rheumatol"},{"key":"2023072622175062000_bib16","doi-asserted-by":"publisher","first-page":"16357","DOI":"10.1073\/pnas.0907996106","article-title":"Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung","volume":"106","author":"Lee","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023072622175062000_bib17","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/ni.2509","article-title":"Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach","volume":"14","author":"Lee","year":"2013","journal-title":"Nat. Immunol"},{"key":"2023072622175062000_bib18","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.immuni.2011.06.014","article-title":"Mapping a dynamic innate immunity protein interaction network regulating type I interferon production","volume":"35","author":"Li","year":"2011","journal-title":"Immunity"},{"key":"2023072622175062000_bib19","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1056\/NEJMoa1312625","article-title":"Activated STING in a vascular and pulmonary syndrome","volume":"371","author":"Liu","year":"2014","journal-title":"N. Engl. J. Med"},{"key":"2023072622175062000_bib20","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa2630","article-title":"Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation","volume":"347","author":"Liu","year":"2015","journal-title":"Science"},{"key":"2023072622175062000_bib21","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"2023072622175062000_bib22","doi-asserted-by":"publisher","first-page":"11902","DOI":"10.1038\/s41598-017-12308-4","article-title":"Double deficiency of Trex2 and DNase1L2 nucleases leads to accumulation of DNA in lingual cornifying keratinocytes without activating inflammatory responses","volume":"7","author":"Manils","year":"2017","journal-title":"Sci. Rep"},{"key":"2023072622175062000_bib23","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/s41586-018-0345-2","article-title":"Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development","volume":"559","author":"Miller","year":"2018","journal-title":"Nature"},{"key":"2023072622175062000_bib24","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1091\/mbc.e07-10-0989","article-title":"The cargo receptors Surf4, endoplasmic reticulum-Golgi intermediate compartment (ERGIC)-53, and p25 are required to maintain the architecture of ERGIC and Golgi","volume":"19","author":"Mitrovic","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"2023072622175062000_bib25","doi-asserted-by":"publisher","first-page":"11932","DOI":"10.1038\/ncomms11932","article-title":"Activation of STING requires palmitoylation at the Golgi","volume":"7","author":"Mukai","year":"2016","journal-title":"Nat. Commun"},{"key":"2023072622175062000_bib26","doi-asserted-by":"crossref","unstructured":"Mukai, K., E.Ogawa, R.Uematsu, Y.Kuchitsu, T.Uemura, S.Waguri, T.Suzuki, N.Dohmae, H.Arai, A.K.Shum, . 2020. Homeostatic regulation of STING by Golgi-to-ER membrane traffic. bioRxiv. https:\/\/doi.org\/10.1101\/2020.05.20.107664 (Preprint posted May 21, 2020)","DOI":"10.1101\/2020.05.20.107664"},{"key":"2023072622175062000_bib27","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/nature07208","article-title":"Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance","volume":"455","author":"Nedjic","year":"2008","journal-title":"Nature"},{"key":"2023072622175062000_bib28","doi-asserted-by":"publisher","first-page":"3289","DOI":"10.4049\/jimmunol.1203086","article-title":"IRF7-dependent IFN-\u03b2 production in response to RANKL promotes medullary thymic epithelial cell development","volume":"190","author":"Otero","year":"2013","journal-title":"J. Immunol"},{"key":"2023072622175062000_bib29","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1165\/ajrcmb.24.5.4333","article-title":"Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression","volume":"24","author":"Ramos","year":"2001","journal-title":"Am. J. Respir. Cell Mol. Biol"},{"key":"2023072622175062000_bib30","doi-asserted-by":"publisher","first-page":"1700403","DOI":"10.1002\/pmic.201700403","article-title":"Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a Positive Regulator of SeV-Induced Innate Immunity","volume":"18","author":"Shang","year":"2018","journal-title":"Proteomics"},{"key":"2023072622175062000_bib31","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/s41590-018-0287-8","article-title":"The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum","volume":"20","author":"Srikanth","year":"2019","journal-title":"Nat. Immunol"},{"key":"2023072622175062000_bib32","doi-asserted-by":"publisher","first-page":"00017","DOI":"10.1183\/23120541.00017-2018","article-title":"Analysis of pulmonary features and treatment approaches in the COPA syndrome","volume":"4","author":"Tsui","year":"2018","journal-title":"ERJ Open Res"},{"key":"2023072622175062000_bib33","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1146\/annurev-immunol-042718-041257","article-title":"Self-Awareness: Nucleic Acid-Driven Inflammation and the Type I Interferonopathies","volume":"37","author":"Uggenti","year":"2019","journal-title":"Annu. Rev. Immunol"},{"key":"2023072622175062000_bib34","doi-asserted-by":"publisher","first-page":"D506","DOI":"10.1093\/nar\/gky1049","article-title":"UniProt: a worldwide hub of protein knowledge","volume":"47","author":"UniProt Consortium","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2023072622175062000_bib35","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.clim.2017.10.001","article-title":"Type I interferon pathway activation in COPA syndrome","volume":"187","author":"Volpi","year":"2018","journal-title":"Clin. Immunol"},{"key":"2023072622175062000_bib36","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1038\/ng.3279","article-title":"COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis","volume":"47","author":"Watkin","year":"2015","journal-title":"Nat. Genet"},{"key":"2023072622175062000_bib37","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/ni.3419","article-title":"Late stages of T cell maturation in the thymus involve NF-\u03baB and tonic type I interferon signaling","volume":"17","author":"Xing","year":"2016","journal-title":"Nat. Immunol"}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20201045\/1789436\/jem_20201045.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20201045\/1789436\/jem_20201045.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T18:18:49Z","timestamp":1690395529000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/217\/11\/e20201045\/151981\/A-defect-in-COPI-mediated-transport-of-STING"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,28]]},"references-count":37,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2020,11,2]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20201045","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.05.20.106500","asserted-by":"object"}]},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,28]]},"article-number":"e20201045"}}