Seigo Terawaki
Department Kawasaki Medical School Kawasaki Medical School, Department of Molecular and Genetic Medicine, Position Assistant Professor with Special Assignment |
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Article types | 原著 |
Language | English |
Peer review | Peer reviewed |
Title | Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses. |
Journal | Formal name:Communications biology Abbreviation:Commun Biol ISSN code:23993642/23993642 |
Domestic / Foregin | Foregin |
Volume, Issue, Page | 3(1),pp.163 |
Author and coauthor | 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 |
Publication date | 2020/04 |
Summary | 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 |