KPNA2 suppresses porcine epidemic diarrhea virus replication by targeting and degrading virus envelope protein through selective autophagy

Porcine epidemic diarrhea virus (PEDV) infection in pigs is characterized by vomiting, dehydration, and diarrhea. Structural proteins of PEDV play crucial roles in viral entry, release, assembly, budding, and host immune regulation. Similar to other viruses, PEDV relies heavily on the host cellular machinery for productive infection. However, the host factors involved in PEDV infection remain unidentified. Thus, this study aims to map the PEDV structural proteins interacting with host factors in Vero cells. Results revealed karyopherin alpha 2 (KPNA2) as a potential host factor to suppress PEDV replication. KPNA2 overexpression in target cells significantly inhibited PEDV infection, whereas KPNA2 silencing by small interfering RNA promoted PEDV infection. Mechanistically, KPNA2 interacted with PEDV E, which led to the degradation of PEDV E protein. These results indicate the probable involvement of KPNA2 in the host antiviral response against PEDV. This study provides novel KPNA2-mediated viral restriction mechanisms in which KPNA2 overexpression suppresses PEDV replication by targeting and degrading the viral E protein by autophagy. KPNA2 may serve as a target in developing strategies to control PEDV infection.IMPORTANCEPorcine epidemic diarrhea, characterized by vomiting, dehydration, and diarrhea, is an acute and highly contagious enteric disease caused by porcine epidemic diarrhea virus (PEDV) in neonatal piglets. This disease has caused large economic losses to the porcine industry worldwide. Thus, identifying the host factors involved in PEDV infection is important to develop novel strategies to control PEDV transmission. This study shows that PEDV infection upregulates karyopherin alpha 2 (KPNA2) expression in Vero and intestinal epithelial (IEC) cells. KPNA2 binds to and degrades the PEDV E protein via autophagy to suppress PEDV replication. These results suggest that KPNA2 plays an antiviral role against PEDV. Specifically, knockdown of endogenous KPNA2 enhances PEDV replication, whereas its overexpression inhibits PEDV replication. Our data provide novel KPNA2-mediated viral restriction mechanisms in which KPNA2 suppresses PEDV replication by targeting and degrading the viral E protein through autophagy. These mechanisms can be targeted in future studies to develop novel strategies to control PEDV infection. Porcine epidemic diarrhea, characterized by vomiting, dehydration, and diarrhea, is an acute and highly contagious enteric disease caused by porcine epidemic diarrhea virus (PEDV) in neonatal piglets. This disease has caused large economic losses to the porcine industry worldwide. Thus, identifying the host factors involved in PEDV infection is important to develop novel strategies to control PEDV transmission. This study shows that PEDV infection upregulates karyopherin alpha 2 (KPNA2) expression in Vero and intestinal epithelial (IEC) cells. KPNA2 binds to and degrades the PEDV E protein via autophagy to suppress PEDV replication. These results suggest that KPNA2 plays an antiviral role against PEDV. Specifically, knockdown of endogenous KPNA2 enhances PEDV replication, whereas its overexpression inhibits PEDV replication. Our data provide novel KPNA2-mediated viral restriction mechanisms in which KPNA2 suppresses PEDV replication by targeting and degrading the viral E protein through autophagy. These mechanisms can be targeted in future studies to develop novel strategies to control PEDV infection.