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

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 identifie...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125101/
https://www.ncbi.nlm.nih.gov/pubmed/32246052
http://dx.doi.org/10.1038/s42003-020-0882-8
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author 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
author_facet 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
author_sort Oikawa, Daisuke
collection PubMed
description 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.
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spelling pubmed-71251012020-04-13 Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses 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 Commun Biol Article 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. Nature Publishing Group UK 2020-04-03 /pmc/articles/PMC7125101/ /pubmed/32246052 http://dx.doi.org/10.1038/s42003-020-0882-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
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
Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses
title Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses
title_full Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses
title_fullStr Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses
title_full_unstemmed Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses
title_short Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses
title_sort molecular bases for hoipins-mediated inhibition of lubac and innate immune responses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125101/
https://www.ncbi.nlm.nih.gov/pubmed/32246052
http://dx.doi.org/10.1038/s42003-020-0882-8
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