{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T18:01:22Z","timestamp":1781373682847,"version":"3.54.1"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81873879"],"award-info":[{"award-number":["81873879"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81801594"],"award-info":[{"award-number":["81801594"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Increased Toll\u2010like receptor 7 (TLR\u20107) signaling leading to the production of type I interferon (IFN) is an important contributor to human systemic lupus erythematosus (SLE). Protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), a molecule that regulates synaptic vesicle recycling, has been linked to TLR\u20107\/TLR\u20109\u2013mediated type I IFN production in humans and mice, but the underlying mechanism is unknown. We undertook this study to explore the pathogenicity and underlying mechanism of a de novo <jats:italic>PACSIN1<\/jats:italic> missense variant identified in a child with SLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>PACSIN1<\/jats:italic> Q59K de novo and null variants were introduced into a human plasmacytoid dendritic cell line and into mice using CRISPR\/Cas9 editing. The effects of the variants on TLR\u20107\/TLR\u20109 signaling in human and mouse cells, as well as <jats:italic>PACSIN1<\/jats:italic> messenger RNA and IFN signature in SLE patients, were assessed using real\u2010time polymerase chain reaction and flow cytometry. Mechanisms were investigated using luciferase reporter assays, RNA interference, coimmunoprecipitation, and immunofluorescence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We established that PACSIN1 forms a trimolecular complex with tumor necrosis factor receptor\u2013associated factor 4 (TRAF4) and TRAF6 that is important for the regulation of type I IFN. The Q59K mutation in PACSIN1 augments binding to neural Wiskott\u2010Aldrich syndrome protein while it decreases binding to TRAF4, leading to unrestrained TRAF6\u2010mediated activation of type I IFN. Intriguingly, PACSIN1 Q59K increased TLR\u20107 but not TLR\u20109 signaling in human cells, leading to elevated expression of IFN\u03b2 and IFN\u2010inducible genes. Untreated SLE patients had high PACSIN1 expression in peripheral blood cells that correlated positively with IFN\u2010related genes. Introduction of the <jats:italic>Pacsin1<\/jats:italic> Q59K mutation into mice caused increased surface TLR\u20107 and TRAIL expression in B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PACSIN1 Q59K increases IFN\u03b2 activity through the impairment of TRAF4\u2010mediated inhibition of TLR\u20107 signaling, possibly contributing to SLE risk.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42416-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42416","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T12:28:37Z","timestamp":1673267317000},"page":"1058-1071","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["De Novo <scp><i>PACSIN1<\/i><\/scp> Gene Variant Found in Childhood Lupus and a Role for <scp>PACSIN1<\/scp>\/<scp>TRAF4<\/scp> Complex in Toll\u2010like Receptor 7 Activation"],"prefix":"10.1002","volume":"75","author":[{"given":"Chengmei","family":"Xie","sequence":"first","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology, Renji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Zhou","sequence":"additional","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology, Renji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicki","family":"Athanasopoulos","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Disease John Curtin School of Medical Research, Acton, Australian Capital Territory  Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Shen","sequence":"additional","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Acton, Australian Capital Territory  Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Disease John Curtin School of Medical Research, Acton, Australian Capital Territory  Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangpeng","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Disease John Curtin School of Medical Research, Acton, Australian Capital Territory  Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetan","family":"Burgio","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Disease John Curtin School of Medical Research, Acton, Australian Capital Territory  Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todor","family":"Arsov","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences University Goce Delchev  Shtip North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian C.","family":"Lungu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology Fundeni Clinical Institute  Bucharest Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology, Renji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Qin","sequence":"additional","affiliation":[{"name":"China\u2010Australia Centre for Personalized Immunology, Department of Rheumatology, Renji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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