テラワキ セイゴウ   Seigo Terawaki
  寺脇 正剛
   所属   川崎医科大学  医学部 基礎医学 分子遺伝医学
   職種   特任講師
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses.
掲載誌名 正式名:Communications biology
略  称:Commun Biol
ISSNコード:23993642/23993642
掲載区分国外
巻・号・頁 3(1),163頁
著者・共著者 Oikawa Daisuke, Sato Yusuke, Ohtake Fumiaki, Komakura Keidai, Hanada Kazuki, Sugawara Koji, Terawaki Seigo, Mizukami Yukari, Phuong Hoang T, Iio Kiyosei, Obika Shingo, Fukushi Masaya, Irie Takashi, Tsuruta Daisuke, Sakamoto Shinji, Tanaka Keiji, Saeki Yasushi, Fukai Shuya, Tokunaga Fuminori
発行年月 2020/04
概要 The NF-κB and interferon antiviral signaling pathways play pivotal roles in inflammatory and innate immune responses. The LUBAC ubiquitin ligase complex, composed of the HOIP, HOIL-1L, and SHARPIN subunits, activates the canonical NF-κB pathway through Met1-linked linear ubiquitination. We identified small-molecule chemical inhibitors of LUBAC, HOIPIN-1 and HOIPIN-8. Here we show that HOIPINs down-regulate not only the proinflammatory cytokine-induced canonical NF-κB pathway, but also various pathogen-associated molecular pattern-induced antiviral pathways. Structural analyses indicated that HOIPINs inhibit the RING-HECT-hybrid reaction in HOIP by modifying the active Cys885, and residues in the C-terminal LDD domain, such as Arg935 and Asp936, facilitate the binding of HOIPINs to LUBAC. HOIPINs effectively induce cell death in activated B cell-like diffuse large B cell lymphoma cells, and alleviate imiquimod-induced psoriasis in model mice. These results reveal the molecular and cellular bases of LUBAC inhibition by HOIPINs, and demonstrate their potential therapeutic uses.
DOI 10.1038/s42003-020-0882-8
PMID 32246052