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タイトル: | Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling |
著者: | Fuseya, Yasuhiro Kadoba, Keiichiro Liu, Xiaoxi Suetsugu, Hiroyuki Iwasaki, Takeshi Ohmura, Koichiro Sumida, Takayuki Kochi, Yuta Morinobu, Akio https://orcid.org/0000-0002-4672-638X (unconfirmed) Terao, Chikashi Iwai, Kazuhiro https://orcid.org/0000-0001-5620-5951 (unconfirmed) |
著者名の別形: | 伏屋, 康寛 門場, 啓一郎 劉, 暁渓 末次, 弘征 岩﨑, 毅 大村, 浩一郎 住田, 孝之 高地, 雄太 森信, 暁雄 寺尾, 知可史 岩井, 一宏 |
発行日: | 8-Feb-2024 |
出版者: | American Society for Clinical Investigation |
誌名: | JCI Insight |
巻: | 9 |
号: | 3 |
論文番号: | e171108 |
抄録: | Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. 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 ΔRING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sjögren's 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 RBCK1/HOIL-1L gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the RBCK1/HOIL-1L 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 RBCK1/HOIL-1L is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease. |
記述: | 自己免疫疾患の発症メカニズムの一端を解明 --自己免疫疾患の新規治療ターゲットへ--. 京都大学プレスリリース. 2024-02-09. |
著作権等: | © 2024, Fuseya et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
URI: | http://hdl.handle.net/2433/287020 |
DOI(出版社版): | 10.1172/jci.insight.171108 |
PubMed ID: | 38329126 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2024-02-09-0 https://insight.jci.org/articles/view/171108 |
出現コレクション: | 学術雑誌掲載論文等 |
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