Seigo Terawaki    Department   Kawasaki Medical School  Kawasaki Medical School, Department of Molecular and Genetic Medicine,    Position   Assistant Professor with Special Assignment
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