Protein Kinase CK2 Acts as a Molecular Brake to Control NADPH Oxidase 1 Activation and Colon Inflammation
| Autor: | Liu, Dan, Marie, Jean-Claude, Pelletier, Anne-Laure, Song, Zhuoyao, Ben-Khemis, Marwa, Boudiaf, Kaouthar, Pintard, Coralie, Leger, Thibaut, Terrier, Samuel, Chevreux, Guillaume, El-Benna, Jamel, Dang, Pham My-Chan |
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| Přispěvatelé: | Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), DANG, Pham My-Chan, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Fougères - ANSES, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), La Ligue Nationale Contre le Cancer, Comité De Paris, grant no.RS18/75-13, INSERM, Labex Inflamex, CNRS and University of Paris. 2022 CK2 Controls NOX1 Activity and Colitis 1093, Chiffoleau, Emmanuelle |
| Rok vydání: | 2022 |
| Předmět: |
protéine kinase
MESH: NADPH Oxidase 1 MESH: Casein Kinase II souris [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity Mice MESH: Colitis toxicité Animals Casein Kinase II [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity Inflammation colon Hepatology Gastroenterology toxicologie MESH: Reactive Oxygen Species protein kinase [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology MESH: Inflammatory Bowel Diseases Colitis Inflammatory Bowel Diseases immunity [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology MESH: Trinitrobenzenesulfonic Acid Trinitrobenzenesulfonic Acid colite NADPH Oxidase 1 tract intestinal intestinal tract Reactive Oxygen Species metabolism immunité |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, 2022, 13 (4), pp.1073-1093. ⟨10.1016/j.jcmgh.2022.01.003⟩ |
| ISSN: | 2352-345X |
| Popis: | International audience; BACKGROUND & AIMS: NADPH oxidase 1 (NOX1) has emerged as a prime regulator of intestinal mucosa immunity and homeostasis. Dysregulation of NOX1 may cause inflammatory bowel disease (IBD). It is not clear how NOX1 is regulated in vivo under inflammatory conditions. We studied the role of CK2 in this process.METHODS: The NOX1 organizer subunit, NADPH oxidase organizer 1 (NOXO1), was immunoprecipitated from cytokine-treated colon epithelial cells, and bound proteins were identified by mass spectrometry analysis. Sites on NOXO1 phosphorylated by CK2 were identified by nanoscale liquid chromatography coupled to tandem mass spectrometry. NOX1 activity was determined in colon epithelial cells and colonoids in the presence or absence of CX-4945, a CK2 specific inhibitor. Acute colitis was induced by administration of trinitrobenzenesulfonic acid in mice treated or not with CX-4945. Colon tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and Western blots. CK2 activity, markers of inflammation, and oxidative stress were assessed.RESULTS: We identified CK2 as a major partner of NOXO1 in colon epithelial cells under inflammatory conditions. CK2 directly binds NOXO1 at the C-terminus containing the Phox homology domain and phosphorylates NOXO1 on several sites. CX-4945 increased ROS generation by NOX1 in human colon epithelial cells and organoids. Strikingly, CK2 activity was reduced in trinitrobenzenesulfonic acid-induced acute colitis, and CX-4945 exacerbated colitis inflammation as shown by increased levels of CXCL1, ROS generation, lipid peroxidation, and colon damage.CONCLUSIONS: The ubiquitous protein kinase CK2 limits NOX1 activity via NOXO1 binding and phosphorylation in colonic epithelial cells and lessens experimental colitis. Loss of CK2 activity during acute colitis results in excessive ROS production, contributing to the pathogenesis. Strategies to activate CK2 could be an effective novel therapeutic approach in IBD. |
| Databáze: | OpenAIRE |
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