Encephalomyocarditis Virus evades IFN-mediated antiviral response by RNF149 targeting JAK1 for ubiquitination and degradation

Encephalomyocarditis virus (EMCV), an important zoonotic pathogen, causes an acute disease characterized primarily by encephalitis and myocarditis. Interferon (IFN) activates the JAK-STAT signaling pathway to induce the expression of interferon-stimulated genes (ISGs), resulting in antiviral effects. However, the mechanism through which EMCV evades the immune system via the IFN-mediated JAK-STAT signaling pathway remains poorly understood. Here, we identified an E3 ubiquitin ligase, RNF149, that is upregulated in EMCV-infected cells. Overexpression of RNF149 inhibited type I IFN-mediated JAK-STAT signaling pathway activation and its antiviral response, enhancing viral replication. Knockout of RNF149 promoted ISGs expression. Notably, RNF149 interacted with JAK1 and downregulated its protein expression through the E3 ubiquitin ligase. RNF149 promoted the K27- and K33-linked ubiquitination of JAK1, which promoted JAK1 degradation through the proteasome pathway. Taken together, these data describe a negative regulatory mechanism involving RNF149 in interferon antiviral activity and provide insights into the mechanism by which EMCV evades host antiviral immunity. These results provide a new strategy for treating viral infections.