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LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP. Here, we show that HOIL-1L \u0394RING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sj\u00f6gren\u2019s syndrome in a female-dominant fashion. Augmented LUBAC activity led to hyperactivation of both lymphoid and myeloid cells. In line with the findings in mice, we sought to identify missense single nucleotide polymorphisms\/variations of the\n                    <jats:italic>RBCK1\/HOIL-1L<\/jats:italic>\n                    gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the\n                    <jats:italic>RBCK1\/HOIL-1L<\/jats:italic>\n                    gene, attenuated HOIL-1L ligase activity and augmented LUBAC-mediated immune signaling, including that mediated by Toll-like receptors. We also found that rs774507518 was enriched significantly in patients with SLE, strongly suggesting that\n                    <jats:italic>RBCK1\/HOIL-1L<\/jats:italic>\n                    is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.171108","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T13:24:38Z","timestamp":1712841878000},"source":"Crossref","is-referenced-by-count":9,"title":["Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3281-6074","authenticated-orcid":true,"given":"Yasuhiro","family":"Fuseya","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology 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