VAPA suppresses BEFV and VSV-induced type I IFNs signaling response by targeting JAK1 for NEDD4-mediated ubiquitin-proteasome degradation.

VAMP-associated protein A (VAPA) binds to various proteins involved in multiple cellular processes, however, its role in the regulation of type I interferons (IFN-I) signaling has not been elucidated. In this study, we demonstrate that VAPA negatively regulates the IFN-I signaling during bovine epidemic fever virus (BEFV) and vesicular stomatitis virus (VSV) infection. Upon treatment with IFN-β, VAPA negatively regulates the JAK-STAT signaling pathway. Further studies show that VAPA inhibits the IFN-I signaling by promoting the degradation of JAK1 through the ubiquitin-proteasome system during BEFV and VSV infection. Mechanistically, VAPA facilitates the interaction between the E3 ubiquitin ligase NEDD4 and JAK1, thereby enhancing the ubiquitination and subsequent degradation of JAK1. Furthermore, viral titers are markedly reduced, and the promoting effect of VAPA on VSV or BEFV replication is attenuated in NEDD4-deficient cells. Taken together, our findings reveal a novel role for VAPA in negatively regulating the IFN-I signaling response and provide a molecular basis for the design of targeted antiviral agents.