Prion-like characteristics of Hepatitis E virus ORF3 protein are associated with virus release and pathogenesis

Hepatitis E virus (HEV) is a common causative agent of acute hepatitis. Due to the shortage of efficient in vitro model, the viral assembly and release processes are still poorly understood. In this study, we found that ORF3, an HEV structural protein showed prion-like properties. The prion domain (PrD) of yeast prion Sup35 could be functionally replaced by HEV-ORF3 and its candidate PrD (cPrD). A single amino acid substitution in the cPrD reduced the aggregation propensity of ORF3 and blocked the function of ORF3 in enhancing the stability of microtubules in HEV-infected cells, thus blocking virion release from the infected cells and resulting in reduced HEV pathogenicity in Mongolian gerbils. These data suggest that HEV-ORF3 is a novel functional prion-like protein which assembles into a filamentous structure for virion release, supporting the hypothesis that the self-propagating properties of prion proteins are widely exploited as epigenetic information carriers in nature. ### Competing Interest Statement The authors have declared no competing interest.