Antagonism of PRDX1 and Japanese encephalitis virus via the autophagy pathway

ABSTRACT Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic infectious agent and causes animal and human illness of the central nervous system. Japanese encephalitis virus inflicts severe harm, yet even with an approved vaccine, prevention and control remain daunting, and the molecular mechanism underlying the virus-host interplay remains incompletely understood. In this study, we found that the host peroxiredoxin 1 (PRDX1) protein inhibits JEV replication. PRDX1 targets nonstructural protein 1 (NS1) of JEV and mediates its degradation via the proteasome and autophagy pathways, thus inhibiting viral replication. By targeting TRAF6, an E3 ligase, the PRDX1 protein catalyzes the ubiquitination of NS1, leading to its recognition by NDP52, a cargo receptor, along with lysosomal degradation. We also found that the JEV NS3 protein can target and degrade PRDX1 to decrease the antiviral function of PRDX1, which is a tactic by which viruses confront the host. In conclusion, these findings showed that selective autophagy has dual functions in the host and JEV: it can degrade viral proteins to inhibit viral replication and host antiviral proteins to promote viral replication. IMPORTANCE Japanese encephalitis virus (JEV) is a flavivirus capable of inducing human encephalitis and dysgenesis in gestating sows. It has an extraordinary ability to hijack cellular systems and evade defenses, establishing infection and spreading it throughout the body to cause disease. During viral infection, the host initiates several antiviral responses and activates various host-restricted factors to resist viral invasion. In this study, we identified PRDX1 as a novel host restrictor that inhibits viral multiplication by binding to TRAF6 (an E3 ubiquitin ligase) and NDP52 (a cargo receptor) to degrade nonstructural protein 1 (NS1) of JEV. We also found that JEV infection can downregulate intracellular PRDX1 expression via nonstructural protein 3 (NS3), thus promoting viral replication. These results revealed that the virus-host interaction is a complex and dynamic process in which viruses restrict and compete with each other.