ARRDC3 promotes lysosome-mediated YAP degradation to inhibit enterovirus replication.

Enterovirus D68 (EV-D68) and enterovirus A71 (EV-A71) are two major types of enteroviruses that pose emerging challenges to public health and have the potential to cause outbreaks, yet their pathogenic mechanisms remain largely unexplored. Arrestin domain containing 3 (ARRDC3) is a vital regulator of glucose metabolism, cancer development, and inflammation. Whether ARRDC3 contributes to innate antiviral immunity is undefined. Here, we found that enterovirus infection induces ARRDC3 expression at both the mRNA and protein levels, thereby inhibiting enterovirus replication. Moreover, we demonstrate that the expression of Yes-associated protein (YAP), a key effector of the Hippo pathway, is severely downregulated by ARRDC3 via lysosomal pathway. YAP facilitates enterovirus replication by suppressing the interferon pathway during the later stage of enterovirus infection, independent of its transcriptional activity. Finally, the ARRDC3-YAP pathway exhibits a broad-spectrum antiviral effect in various viral infections, including those caused by human parainfluenza virus type 3 (HPIV3) and vesicular stomatitis virus (VSV). Collectively, our results identify the critical role of ARRDC3 and its negative regulatory effect on YAP in the innate antiviral response, suggesting a novel therapeutic strategy against virus infection.