TRIM65 regulates innate immune signaling by enhancing K6-linked ubiquitination of IRF3 and its chromatin recruitment
Danae Fonseca,
Giuseppe Pisanelli,
Rocío Seoane,
Lisa Miorin,
Adolfo García-Sastre
Affiliations
Danae Fonseca
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
Giuseppe Pisanelli
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
Rocío Seoane
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
Lisa Miorin
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; Corresponding author
Adolfo García-Sastre
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; Corresponding author
Summary: 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.
