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

• Published in: Cell reports (Cambridge) Vol. 43; no. 12; p. 114960
• Main Authors: Fonseca, Danae, Pisanelli, Giuseppe, Seoane, Rocío, Miorin, Lisa, García-Sastre, Adolfo
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-12-2024; Elsevier
• Subjects: chromatin; CP: Immunology; IFNβ promoter; innate immunity; IRF3; K6-linked ubiquitination; TRIM65; CP: Immunology; IRF3; innate immunity; K6-linked ubiquitination; IFNβ promoter; chromatin; TRIM65
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114960

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.
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•TRIM65 is a positive regulator of innate immune signaling•TRIM65 boosts IFNβ and ISGs production downstream of RNA and DNA sensing•TRIM65 enhances IRF3 chromatin recruitment•TRIM65 mediates K6-linked ubiquitination of IRF3 to promote activation of the IFNβ promoter
Fonseca et al. show that TRIM65 is a positive regulator of the innate immune response upon virus infection. Mechanistically, TRIM65 activation releases its BBCC domain, facilitating IRF3 binding and K6-linked ubiquitination. This results in enhanced IRF3 chromatin recruitment and activation of the IFNβ promoter leading to a robust antiviral response.