TRIM47 catalyzes MAVS SUMOylation to safeguard chronic viral infections and tissue inflammation.

Abstract

Background: Chronic tissue inflammation causes progressive tissue damage, organ dysfunction, and increased susceptibility to inflammatory diseases. Viral infections are major drivers of this process, but the molecular mechanisms linking antiviral immune responses to persistent inflammation and tissue pathology remain poorly understood.

Methods: The function of TRIM47 was examined using primary macrophages and mouse models of RNA virus infection. Alveolar macrophages, peritoneal macrophages, and bone marrow-derived macrophages (BMDM) from wild-type and Trim47-deficient (Trim47-KO) mice were treated with RNA viruses or RNA mimics, and antiviral cytokine production was quantified. Sublethal reovirus and influenza A virus infection mouse models were used to evaluate survival, cytokine responses, and viral titers in vivo. Liquid chromatography-tandem mass spectrometry (LC-MS) was used to identify TRIM47-interacting proteins. Molecular and biochemical assays were used to examine post-translational modification, aggregation and activation of mitochondrial antiviral-signaling protein (MAVS).

Results: TRIM47 was highly expressed in macrophages, and TRIM47 deficiency in BMDM markedly reduced type I interferon (IFN-I) production following RNA virus infection or RNA mimics stimulation. In sublethal RNA virus infection mouse models, Trim47-KO mice exhibited reduced survival, impaired IFN-I responses, higher viral titers, increased inflammatory cell infiltration and tissue inflammation including myocarditis compared to wild-type mice. Mechanistically, TRIM47 interacted with MAVS and promoted SUMO1-mediated MAVS SUMOylation at K297 and K348, thereby enhancing MAVS aggregation and activation and driving robust IFN-I, IL-1β and IL-18 production in macrophages.

Conclusions: These findings establish TRIM47 as a molecular switch of MAVS activation and antiviral cytokine responses in macrophages, highlighting its role in restricting RNA virus infection and mitigating inflammation. This study provides mechanistic insight into host pathways that may be therapeutically leveraged in chronic viral inflammation.