Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses

• DOI: 10.1038/s42003-020-0882-8
• Publication Date: 2020-04-03T10:07:13Z
• Authors: Daisuke Oikawa; Yusuke Sato; Fumiaki Ohtake; Keidai Komakura; Kazuki Hanada; Koji Sugawara; Seigo Terawaki; Yukari Mizukami; Hoang T. Phuong; Kiyosei Iio; Shingo Obika; Masaya Fukushi; Takashi Irie; Daisuke Tsuruta; Shinji Sakamoto; Keiji Tanaka; Yasushi Saeki; Shuya Fukai; Fuminori Tokunaga
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; 0303 health sciences; Imiquimod; Molecular Structure; Anti-Inflammatory Agents; Intracellular Signaling Peptides and Proteins; Antineoplastic Agents; Apoptosis; Article; Immunity, Innate; 3. Good health; Disease Models, Animal; Jurkat Cells; Mice; 03 medical and health sciences; HEK293 Cells; A549 Cells; Animals; Humans; Female; Lymphoma, Large B-Cell, Diffuse; Enzyme Inhibitors; Inflammation Mediators; HeLa Cells

AbstractThe 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.