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

A549 Cells Animals Anti-Inflammatory Agents / chemistry Antineoplastic Agents / chemistry Apoptosis / drug effects Disease Models, Animal Enzyme Inhibitors / chemistry Female HEK293 Cells HeLa Cells Humans Imiquimod Immunity, Innate / drug effects Inflammation Mediators / metabolism Intracellular Signaling Peptides and Proteins / genetics Jurkat Cells Lymphoma, Large B-Cell, Diffuse / drug therapy Mice Mice, Inbred BALB C Molecular Structure Psoriasis / chemically induced Signal Transduction Structure-Activity Relationship Transcription Factors / genetics Ubiquitin-Protein Ligases / antagonists & inhibitors Ubiquitins / genetics

Journal

Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179

Informations de publication

Date de publication:
03 04 2020
Historique:
received: 10 08 2019
accepted: 27 02 2020
entrez: 5 4 2020
pubmed: 5 4 2020
medline: 16 6 2021
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s42003-020-0882-8 PMID: 32246052 PMC: PMC7125101
pubmed: 32246052
doi: 10.1038/s42003-020-0882-8
pii: 10.1038/s42003-020-0882-8
pmc: PMC7125101
doi:

Substances chimiques

Anti-Inflammatory Agents 0
Antineoplastic Agents 0
Enzyme Inhibitors 0
Inflammation Mediators 0
Intracellular Signaling Peptides and Proteins 0
SHARPIN protein, human 0
Sipl1 protein, mouse 0
Transcription Factors 0
Ubiquitins 0
RBCK1 protein, human EC 2.3.2.27
RNF31 protein, human EC 2.3.2.27
Rbck1 protein, mouse EC 2.3.2.27
Rnf31 protein, mouse EC 2.3.2.27
Ubiquitin-Protein Ligases EC 2.3.2.27
Imiquimod P1QW714R7M

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

163

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Auteurs

Daisuke Oikawa (D)

Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.
ORCID: 0000-0002-2897-1779

Yusuke Sato (Y)

Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
Synchrotron Radiation Research Organization, The University of Tokyo, Tokyo, Japan.
Center for Research on Green Sustainable Chemistry, Tottori University, Tottori, Japan.
ORCID: 0000-0001-8495-8950

Fumiaki Ohtake (F)

Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan.

Keidai Komakura (K)

Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Department of Dermatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Kazuki Hanada (K)

Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., Kanagawa, Japan.
ORCID: 0000-0001-7554-107X

Koji Sugawara (K)

Department of Dermatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
ORCID: 0000-0003-1662-3272

Seigo Terawaki (S)

Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan.
ORCID: 0000-0001-6019-1628

Yukari Mizukami (Y)

Department of Dermatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
ORCID: 0000-0002-4422-2049

Hoang T Phuong (HT)

Department of Dermatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Kiyosei Iio (K)

Chemical Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., Osaka, Japan.

Shingo Obika (S)

Chemical Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., Osaka, Japan.

Masaya Fukushi (M)

Department of Virology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
ORCID: 0000-0002-1315-2877

Takashi Irie (T)

Department of Virology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
ORCID: 0000-0003-3765-8482

Daisuke Tsuruta (D)

Department of Dermatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
ORCID: 0000-0001-6283-0251

Shinji Sakamoto (S)

Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., Kanagawa, Japan.
ORCID: 0000-0003-2480-2940

Keiji Tanaka (K)

Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Yasushi Saeki (Y)

Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
ORCID: 0000-0002-9202-5453

Shuya Fukai (S)

Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
Synchrotron Radiation Research Organization, The University of Tokyo, Tokyo, Japan.
ORCID: 0000-0002-1241-1443

Fuminori Tokunaga (F)

Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka, Japan. ftokunaga@med.osaka-cu.ac.jp.
ORCID: 0000-0003-3626-9119

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules A549 › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-inflammatoires › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HeLa › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinoléines › Aminoquinoléines › Imiquimod › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Immunité innée › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Facteurs biologiques › Médiateurs de l'inflammation › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Cellules Jurkat › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Lymphome B › Lymphome B diffus à grandes cellules › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Molecular bases for HOIPINs-mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée BALB C › Molecular bases for HOIPINs-mediated...
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