CRM1-spike-mediated nuclear export of hepatitis B virus encapsidated viral RNA

Ching-Chun Yang; Chih-Hsu Chang; Heng-Li Chen; Ming-Chieh Chou; Ching-Jen Yang; Ren-Shiang Jhou; Er-Yi Huang; Hung-Cheng Li; Ching-Shu Suen; Ming-Jing Hwang; Chiaho Shih

doi:10.1016/j.celrep.2022.110472

CRM1-spike-mediated nuclear export of hepatitis B virus encapsidated viral RNA

Cell Rep. 2022 Mar 8;38(10):110472. doi: 10.1016/j.celrep.2022.110472.

Authors

Affiliations

¹ Taiwan International Graduate Program (TIGP) in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 112, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
² Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
³ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁵ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: cshih@kmu.edu.tw.

PMID: 35263598
DOI: 10.1016/j.celrep.2022.110472

Abstract

Hepatitis B virus (HBV) is a global pathogen. We report here that the cellular CRM1 machinery can mediate nuclear export of entire HBV core (HBc) particles containing encapsidated viral RNAs. Two CRM1-mediated nuclear export signals (NES^CRM1) cluster at the conformationally flexible spike tips of HBc particles. Mutant NES^CRM1 capsids exhibit strongly reduced associations with CRM1 and nucleoporin358 in vivo. CRM1 and NXF1 machineries mediate nuclear export of HBc particles independently. Inhibition of nuclear export has pleiotropic consequences, including nuclear accumulation of HBc particles, a significant reduction of encapsidated viral RNAs in the cytoplasm but not in the nucleus, and barely detectable viral DNA. We hypothesize an HBV life cycle where encapsidation of the RNA pregenome can initiate early in the nucleus, whereas DNA genome maturation occurs mainly in the cytoplasm. We identified a druggable target for HBV by blocking its intracellular trafficking.

Keywords: CRM1; HBV core protein (HBc); HBc capsids; NXF1; encapsidation; hepatitis B virus (HBV); nuclear export; pregenomic RNA (pgRNA); spike; therapeutics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus / genetics
Capsid / metabolism
Cytoplasm / metabolism
Hepatitis B virus* / genetics
RNA, Viral* / genetics
RNA, Viral* / metabolism

Substances

RNA, Viral