RING finger protein 5 is a key anti-FMDV host factor through inhibition of virion assembly.

Foot-and-mouth disease virus (FMDV) are small, icosahedral viruses that cause serious clinical symptoms in livestock. The FMDV VP1 protein is a key structural component, facilitating virus entry. Here, we find that the E3 ligase RNF5 interacts with VP1 and targets it for degradation through ubiquitination at the lys200 of VP1, ultimately inhibiting virus replication. Mutations at this lysine site have been found to increase the replication of FMDV in mice. Importantly, the RNF5 pharmacological activator Analog-1 alleviates disease development in a mouse infection model. Furthermore, RNF5 recognizes the VP1 protein from several picornaviruses, suggesting that targeting RNF5 may be a broad-spectrum antiviral strategy. These findings shed light on the role of the ubiquitin-proteasome system in controlling virus replication, offering potential new strategies for treating viral infections. Author summary: Elucidation of the host factors that modulate the FMDV lifecycle is vital for developing antiviral drugs and vaccines. In this study, we show that RNF5 acts as a cell-intrinsic antiviral effector by inhibiting multiple picornaviruses through targeting the viral VP1 protein for ubiquitination and subsequent degradation by the proteasome. Further investigation revealed that the Lys200 of VP1 is a specific site for RNF5-mediated ubiquitination. Disruption of this ubiquitination site led to increased replication of FMDV both in vitro and in vivo. The use of Analog-1, a pharmacological activator of RNF5, was shown to mitigate disease progression in a mouse infection model. These findings unveil a strategy for targeting picornavirus replication and offer insights that could aid in the development of new therapeutics for picornavirus infections. [ABSTRACT FROM AUTHOR]