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Journal article
Hepatitis B virus modulates store-operated calcium entry to enhance viral replication in primary hepatocytes
PloS one, v 12(2), pp e0168328-e0168328
02 Feb 2017
PMID: 28151934
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Many viruses modulate calcium (Ca2+) signaling to create a cellular environment that is more permissive to viral replication, but for most viruses that regulate Ca2+ signaling, the mechanism underlying this regulation is not well understood. The hepatitis B virus (HBV) HBx protein modulates cytosolic Ca2+ levels to stimulate HBV replication in some liver cell lines. A chronic HBV infection is associated with life-threatening liver diseases, including hepatocellular carcinoma (HCC), and HBx modulation of cytosolic Ca2+ levels could have an important role in HBV pathogenesis. Whether HBx affects cytosolic Ca2+ in a normal hepatocyte, the natural site of an HBV infection, has not been addressed. Here, we report that HBx alters cytosolic Ca2+ signaling in cultured primary hepatocytes. We used single cell Ca2+ imaging of cultured primary rat hepatocytes to demonstrate that HBx elevates the cytosolic Ca2+ level in hepatocytes following an IP3-linked Ca2+ response; HBx effects were similar when expressed alone or in the context of replicating HBV. HBx elevation of the cytosolic Ca2+ level required extracellular Ca2+ influx and store-operated Ca2+ (SOC) entry and stimulated HBV replication in hepatocytes. We used both targeted RT-qPCR and transcriptome- wide RNAseq analyses to compare levels of SOC channel components and other Ca2+ signaling regulators in HBV-expressing and control hepatocytes and show that the transcript levels of these various proteins are not affected by HBV. We also show that HBx regulation of SOC-regulated Ca2+ accumulation is likely the consequence of HBV modulation of a SOC channel regulatory mechanism. In support of this, we link HBx enhancement of SOC-regulated Ca2+ accumulation to Ca2+ uptake by mitochondria and demonstrate that HBx stimulates mitochondrial Ca2+ uptake in primary hepatocytes. The results of our study may provide insights into viral mechanisms that affect Ca2+ signaling to regulate viral replication and virus-associated diseases.
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Details
- Title
- Hepatitis B virus modulates store-operated calcium entry to enhance viral replication in primary hepatocytes
- Creators
- Jessica C. Casciano - Drexel UniversityNicholas J. Duchemin - Drexel UniversityR. Jason Lamontagne - Drexel Univ, Program Microbiol & Immunol, Grad Sch Biomed Sci & Profess Studies, Coll Med, Philadelphia, PA 19104 USALaura F. Steel - Drexel UniversityMichael J. Bouchard - Drexel University
- Publication Details
- PloS one, v 12(2), pp e0168328-e0168328
- Publisher
- Public Library Science
- Number of pages
- 26
- Grant note
- F31CA171850 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Microbiology and Immunology
- Web of Science ID
- WOS:000396161200004
- Scopus ID
- 2-s2.0-85011362871
- Other Identifier
- 991019168612804721
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- Web of Science research areas
- Biochemistry & Molecular Biology