TRIM65 regulates innate immune signaling by enhancing K6-linked ubiquitination of IRF3 and its chromatin recruitment.

Autor:	Fonseca D; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Pisanelli G; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Veterinary Medicine and Animal Production, University of Naples Federico II, via F. Delpino 1, 80137 Naples, Italy., Seoane R; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Miorin L; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: lisa.miorin@mssm.edu., García-Sastre A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: adolfo.garcia-sastre@mssm.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Nov 23; Vol. 43 (12), pp. 114960. Date of Electronic Publication: 2024 Nov 23.
DOI:	10.1016/j.celrep.2024.114960
Abstrakt:	Viral infection triggers a rapid and effective cellular response primarily mediated by interferon β (IFNβ), which induces an antiviral state through complex signaling cascades. To maintain a robust antiviral response while preventing excessive activation, the induction of IFNβ and downstream signaling are tightly regulated. Members of the tripartite-motif (TRIM) family of E3 ubiquitin (Ub) ligases play crucial roles in modulating these processes. In this study, we demonstrate that TRIM65 interacts with interferon regulatory factor 3 (IRF3), a key transcription factor downstream of multiple innate immune signaling pathways, to regulate type-I IFN production. Specifically, TRIM65 activation enables interaction of TRIM65 BBCC domain with the IAD domain of IRF3. This interaction increases K6-linked ubiquitination of IRF3, enhancing IRF3 recruitment to chromatin and subsequent binding to the IFNβ promoter. This process boosts the expression of IFNβ and interferon-stimulated genes (ISGs), thereby strengthening the control of viral infection. Competing Interests: Declaration of interests The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories, and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, Pfizer, and Prosetta, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astrazeneca. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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