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An Arginine-Rich Motif in the ORF2 capsid protein regulates the hepatitis E virus lifecycle and interactions with the host cell

Hepatitis E virus (HEV) is the major cause of acute viral hepatitis worldwide. Although infection with HEV is usually self-resolving, it can cause up to 30% mortality in pregnant women and leads to a chronic infection in immunocompromised patients. There is no specific treatment nor universal vaccine to fight against this virus.

Few years ago, we developed an efficient cell culture system for HEV which allows for studying the molecular and cellular mechanisms of the HEV lifecycle. This model notably enabled the pioneering demonstration that, during its lifecycle, HEV produces at least 3 forms of its ORF2 capsid protein: infectious ORF2 (ORF2i), glycosylated ORF2 (ORF2g), and cleaved ORF2 (ORF2c). These ORF2 forms perform distinct functions in the HEV lifecycle. The ORF2i protein is the structural component of infectious particles whereas the ORF2g/c proteins are not associated with infectious material but likely act as a humoral immune decoy that inhibits antibody-mediated neutralization. The ORF2g/c proteins are secreted in large amounts in culture supernatant and are the most abundant antigens detected in patient sera.

In the study of Hervouet, Ferrié, Ankavay et al., we deciphered the molecular determinants of ORF2 multifunctionality. We identified an arginine-rich motif (ARM) located in the ORF2 N-terminal region that controls the subcellular localization, the fate, the maturation and functions of ORF2 forms. It also promotes ORF2-host cell interactions. Our observations highlighted the ORF2 ARM as a unique central regulator of ORF2 addressing that finely controls the HEV lifecycle. Thus, our study enabled the pioneering demonstration that HEV developed a master strategy to condense multiple information into only five amino acid residues of its capsid protein. This strategy is likely also exploited by other pathogens.

Hervouet, K.*, Ferrié, M.*, Ankavay, M.*, et al. PLoS Pathog. 2022 Aug 25;18(8):e1010798. doi: 10.1371/journal.ppat.1010798.

PloS Pathogens journal