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

Qiang Ding, Brigitte Heller, Juan M.V. Capuccino, Bokai Song, Ila Nimgaonkar, Gabriela Hrebikova, Jorge E. Contreras, Alexander Ploss

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1147-1152
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number5
DOIs
StatePublished - Jan 31 2017

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Drug development
  • Hepatitis E
  • Hepatitis E virus
  • Virion release
  • Viroporin

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