Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles.

TitleHepatitis E virus ORF3 is a functional ion channel required for release of infectious particles.
Publication TypeJournal Article
Year of Publication2017
AuthorsDing, Q, Heller, B, Capuccino, JMV, Song, B, Nimgaonkar, I, Hrebikova, G, Contreras, JE, Ploss, A
JournalProc Natl Acad Sci U S A
Volume114
Issue5
Pagination1147-1152
Date Published2017 01 31
ISSN1091-6490
KeywordsAmino Acid Motifs, Amino Acid Sequence, Amino Acid Substitution, Animals, Endoplasmic Reticulum, Gene Deletion, HEK293 Cells, Hep G2 Cells, Hepatitis E virus, Humans, Ion Channels, Ion Transport, Oocytes, Patch-Clamp Techniques, Protein Domains, Recombinant Fusion Proteins, Structure-Activity Relationship, Viral Matrix Proteins, Viral Proteins, Virus Release, Virus Replication, Xenopus laevis
Abstract

<p>Hepatitis E virus (HEV) is the leading cause of enterically transmitted viral hepatitis globally. Of HEV's three ORFs, the function of ORF3 has remained elusive. Here, we demonstrate that via homophilic interactions ORF3 forms multimeric complexes associated with intracellular endoplasmic reticulum (ER)-derived membranes. HEV ORF3 shares several structural features with class I viroporins, and the function of HEV ORF3 can be maintained by replacing it with the well-characterized viroporin influenza A virus (IAV) matrix-2 protein. ORF3's ion channel function is further evidenced by its ability to mediate ionic currents when expressed in Xenopus laevis oocytes. Furthermore, we identified several positions in ORF3 critical for its formation of multimeric complexes, ion channel activity, and, ultimately, release of infectious particles. Collectively, our data demonstrate a previously undescribed function of HEV ORF3 as a viroporin, which may serve as an attractive target in developing direct-acting antivirals.</p>

DOI10.1073/pnas.1614955114
Alternate JournalProc Natl Acad Sci U S A
PubMed ID28096411
PubMed Central IDPMC5293053