POLM inhibits porcine epidemic diarrhea virus replication by degrading multiple viral structural proteins

Porcine epidemic diarrhea, as a porcine epidemic diarrhea virus (PEDV)-induced infectious intestinal condition typified by diarrhea, emesis, dehydration, and anorexia, leads to death rates as high as 100% among suckling piglets. Given the existing commercial vaccines, it is essential to study host-virus interactions and formulate efficient anti-viral regimes. This study concerned a host factor POLM (a DNA polymerase family member) that exerts an anti-viral effect against PEDV proliferation. Our results indicated that POLM expression was increased following PEDV infection and was regulated by the transcription factor FOXA1. In addition, our findings indicated that POLM targeted and degraded PEDV structural proteins (N, S2, and M) by the autophagy pathway to inhibit PEDV proliferation. POLM could recruit the E3 ubiquitination ligase MARCH8 for N, S2, and M protein ubiquitination, which was subsequently recognized by p62, a cargo receptor, for translocation to the autophagic lysosome, therefore degrading the N, S2, and M proteins and preventing PEDV proliferation. In summary, we showed a novel therapeutic target for combating PEDV, i.e., using the POLM-MARCH8-p62-autophagosome pathway to degrade the PEDV N, S2, and M proteins.IMPORTANCEPEDV is a coronavirus that causes high mortality in piglets, which poses significant economic damage to swine farming. During PEDV infection, the host cells may promote the natural anti-viral immune response to suppress viral replication through a variety of potential host factors. In this study, we found upregulation of a host factor POLM by FOXA1 (a transcription factor) during PEDV infection. It was indicated that POLM could be a new anti-viral protein against the PEDV replication, which interacted with MARCH8 (an E3 ubiquitin ligase) and p62 (a cargo receptor) to facilitate the PEDV N, S2, and M protein degradation via the autophagy process. Apart from elucidating a previously unidentified anti-viral function of POLM, this study also provides a novel perspective for studying host anti-viral factors that act as regulators of anti-PEDV protein degrading pathways.