Hepatitis B virus virion secretion is a CRM1-spike-mediated late event.

Autor: Su PY; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Road, Sanmin, 80708, Kaohsiung, Taiwan.; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Yen SB; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Road, Sanmin, 80708, Kaohsiung, Taiwan.; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Yang CC; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Chang CH; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan., Lin WC; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Shih C; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Road, Sanmin, 80708, Kaohsiung, Taiwan. cshih@kmu.edu.tw.; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. cshih@kmu.edu.tw.
Jazyk: angličtina
Zdroj: Journal of biomedical science [J Biomed Sci] 2022 Jun 21; Vol. 29 (1), pp. 44. Date of Electronic Publication: 2022 Jun 21.
DOI: 10.1186/s12929-022-00827-w
Abstrakt: Background: Hepatitis B virus (HBV) is a major human pathogen worldwide. To date, there is no curative treatment for chronic hepatitis B. The mechanism of virion secretion remains to be investigated. Previously, we found that nuclear export of HBc particles can be facilitated via two CRM1-specific nuclear export signals (NES) at the spike tip.
Methods: In this study, we used site-directed mutagenesis at the CRM1 NES, as well as treatment with CRM1 inhibitors at a low concentration, or CRM1-specific shRNA knockdown, in HBV-producing cell culture, and measured the secretion of various HBV viral and subviral particles via a native agarose gel electrophoresis assay. Separated HBV particles were characterized by Western blot analysis, and their genomic DNA contents were measured by Southern blot analysis. Secreted extracellular particles were compared with intracellular HBc capsids for DNA synthesis and capsid formation. Virion secretion and the in vivo interactions among HBc capsids, CRM1 and microtubules, were examined by proximity ligation assay, immunofluorescence microscopy, and nocodazole treatment.
Results: We report here that the tip of spike of HBV core (HBc) particles (capsids) contains a complex sensor for secretion of both HBV virions and naked capsids. HBV virion secretion is closely associated with HBc nuclear export in a CRM1-dependent manner. At the conformationally flexible spike tips of HBc particles, NES motifs overlap extensively with motifs important for secretion of HBV virions and naked capsids.
Conclusions: We provided experimental evidence that virions and naked capsids can egress via two distinct, yet overlapping, pathways. Unlike the secretion of naked capsids, HBV virion secretion is highly CRM1- and microtubule-dependent. CRM1 is well known for its involvement in nuclear transport in literature. To our knowledge, this is the first report that CRM1 is required for virion secretion. CRM1 inhibitors could be a promising therapeutic candidate for chronic HBV patients in clinical medicine.
(© 2022. The Author(s).)
Databáze: MEDLINE
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