TY - JOUR
T1 - Hepatitis e virus ORF3 is a functional ion channel required for release of infectious particles
AU - Ding, Qiang
AU - Heller, Brigitte
AU - Capuccino, Juan M.V.
AU - Song, Bokai
AU - Nimgaonkar, Ila
AU - Hrebikova, Gabriela
AU - Contreras, Jorge E.
AU - Ploss, Alexander
PY - 2017/1/31
Y1 - 2017/1/31
N2 - 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.
AB - 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.
KW - Drug development
KW - Hepatitis E
KW - Hepatitis E virus
KW - Virion release
KW - Viroporin
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U2 - 10.1073/pnas.1614955114
DO - 10.1073/pnas.1614955114
M3 - Article
C2 - 28096411
AN - SCOPUS:85011303864
SN - 0027-8424
VL - 114
SP - 1147
EP - 1152
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -