Coronavirus accessory protein ORF3 biology and its contribution to viral behavior and pathogenesis

Coronavirus porcine epidemic diarrhea virus (PEDV) is classified in the genus Alphacoronavirus, family Coronaviridae that encodes the only accessory protein, ORF3 protein. However, how ORF3 contributes to viral pathogenicity, adaptability, and replication is obscure. In this review, we summarize current knowledge and identify gaps in many aspects of ORF3 protein in PEDV, with emphasis on its unique biological features, including membrane topology, Golgi retention mechanism, potential intrinsic disordered property, functional motifs, protein glycosylation, and codon usage phenotypes related to genetic evolution and gene expression. In addition, we propose intriguing questions related to ORF3 protein that we hope to stimulate further studies and encourage collaboration among virologists worldwide to provide constructive knowledge about the unique characteristics and biological functions of ORF3 protein, by which their potential role in clarifying viral behavior and pathogenesis can be possible.