SHFL inhibits enterovirus A71 infection by triggering degradation of viral 3Dpol protein via the ubiquitin-proteasome pathway

Enterovirus A71 (EV-A71) is a highly contagious virus that poses a major threat to global health, representing the primary etiological agent for hand-foot and mouth disease (HFMD) and neurological complications. It has been established that interferon signaling is critical to establishing a robust antiviral state in host cells, mainly mediated through the antiviral effects of numerous interferon-stimulated genes (ISGs). The host restriction factor SHFL is a novel ISG with broad antiviral activity against various viruses through diverse underlying molecular mechanisms. Although SHFL is widely acknowledged for its broad-spectrum antiviral activity, it remains elusive whether SHFL inhibits EV-A71. In this work, we validated that EV-A71 triggers the upregulation of SHFL both in cell lines and in a mouse model. Knockdown and overexpression of SHFL in EVA71-infected cells suggested that this factor could markedly suppress EV-A71 replication. Our findings further revealed an intriguing mechanism of SHFL that it could interact with the nonstructural proteins 3Dpol of EV-A71 and promoted the degradation of 3Dpol through the ubiquitin-proteasome pathway. Furthermore, the zinc-finger domain and the 36 amino acids (164-199) of SHFL were crucial to the interaction between SHFL and EV-A71 3Dpol. Overall, these findings broadened our understanding of the pivotal roles of SHFL in the interaction between the host and EV-A71.

Automated summary

Enterovirus A71 (EV-A71) is a major global health threat and it has been found that the host restriction factor SHFL can inhibit EV-A71 replication through interacting with its 3Dpol protein. This study validated the upregulation of SHFL in response to EV-A71 infection and identified the molecular mechanism by which SHFL promotes the degradation of EV-A71 3Dpol via the ubiquitin-proteasome pathway. These findings greatly enhance our understanding of the interaction between host and EV-A71.