The E3-ligase TRIM7 acts as an antiviral factor by ubiquitinating the SARS-CoV-2 membrane protein to limit apoptosis and virus replication

Abstract

Cytokines, such as type-I Interferons (IFN-I), are essential to mount an effective antiviral response. The production of IFN-I is regulated by multiple mechanisms, including ubiquitination of host signaling factors. However, viruses can hijack the ubiquitin (Ub) system to promote viral replication. For example, we recently reported that the E3-Ub ligase TRIM7 ubiquitinates the envelope protein of Zika virus, which increases virus binding to its receptor favoring virus entry. Previous studies suggest that TRIM7 may play dual roles during infection by promoting or inhibiting IFN-I induction depending on the conditions. Here, we used our recently generated Trim7−/− mice to study its physiological role during SARS-CoV-2 (SCoV2) infection. We found that Trim7−/− mice have increased weight loss and lung virus titers compared to WT controls upon infection with SCoV2. We also found a dysregulated innate immune response, which included increased IFN-I induction and reduced neutrophil recruitment and production of inflammatory cytokines such as IL-6 in Trim7−/− mice. We observed a higher frequency of apoptotic cells in Trim7−/− compared to WT mice, specifically in CD45− lung epithelial cells. Mechanistically, using co-immunoprecipitation studies, we confirmed previous reports that TRIM7 interacts with the viral membrane protein (M), which can cause apoptosis. Using recombinant mutants that lack ubiquitination sites on M, we found that TRIM7-mediated ubiquitination of M protects cells against death. This suggests that TRIM7 restricts SCoV2 infection via a novel non-degradative mechanism involving ubiquitination of M. Understanding the role of TRIM7 in inhibiting SCoV2 replication could help develop treatments for COVID-19. Supported by grants from NIH R01 AI166668