Hepatitis C virus infection restricts human LINE-1 retrotransposition in hepatoma cells
| Autor: | Van Nguyen-Dinh, Gerald G. Schumann, Eva Herker, Anja Schöbel |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
RNA viruses
L1 Retrotransposon Hepacivirus medicine.disease_cause Biochemistry 0302 clinical medicine Lipid droplet Macromolecular Structure Analysis Biology (General) Poly-ADP-Ribose Binding Proteins Pathology and laboratory medicine 0303 health sciences Gene knockdown DNA methylation Lipid Analysis Hepatitis C virus Liver Neoplasms virus diseases Transfection Medical microbiology Hepatitis C Lipids Chromatin Precipitation Techniques Nucleic acids RNA Recognition Motif Proteins Ribonucleoproteins 030220 oncology & carcinogenesis Viruses Epigenetics Pathogens DNA modification RNA Helicases Chromatin modification Research Article Chromosome biology Cell biology Carcinoma Hepatocellular Immunoprecipitation QH301-705.5 Immunoblotting Immunology Molecular Probe Techniques Biology Cytoplasmic Granules Research and Analysis Methods Microbiology 03 medical and health sciences Stress granule Cell Line Tumor Virology Genetics medicine Humans Molecular Biology Techniques Molecular Biology 030304 developmental biology Medicine and health sciences Flaviviruses DNA Helicases Organisms Viral pathogens Biology and Life Sciences Proteins Lipid Droplets DNA RC581-607 Luciferase Lipid analysis Hepatitis viruses digestive system diseases Microbial pathogens Long Interspersed Nucleotide Elements Parasitology Gene expression Immunologic diseases. Allergy |
| Zdroj: | PLoS Pathogens, Vol 17, Iss 4, p e1009496 (2021) PLoS Pathogens PLoS pathogens, 17(4):e1009496 |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | LINE-1 (L1) retrotransposons are autonomous transposable elements that can affect gene expression and genome integrity. Potential consequences of exogenous viral infections for L1 activity have not been studied to date. Here, we report that hepatitis C virus (HCV) infection causes a significant increase of endogenous L1-encoded ORF1 protein (L1ORF1p) levels and translocation of L1ORF1p to HCV assembly sites at lipid droplets. HCV replication interferes with retrotransposition of engineered L1 reporter elements, which correlates with HCV RNA-induced formation of stress granules and can be partially rescued by knockdown of the stress granule protein G3BP1. Upon HCV infection, L1ORF1p localizes to stress granules, associates with HCV core in an RNA-dependent manner and translocates to lipid droplets. While HCV infection has a negative effect on L1 mobilization, L1ORF1p neither restricts nor promotes HCV infection. In summary, our data demonstrate that HCV infection causes an increase of endogenous L1 protein levels and that the observed restriction of retrotransposition of engineered L1 reporter elements is caused by sequestration of L1ORF1p in HCV-induced stress granules. Author summary Members of the Long Interspersed Nuclear Element 1 (LINE-1, L1) class of retrotransposons account for ~17% of the human genome and include ~100–150 intact L1 loci that are still functional. L1 mobilization is known to affect genomic integrity, thereby leading to disease-causing mutations, but little is known about the impact of exogenous viral infections on L1 and vice versa. While L1 retrotransposition is controlled by various mechanisms including CpG methylation, hypomethylation of L1 has been observed in hepatocellular carcinoma tissues of hepatitis C virus (HCV)-infected patients. Here, we demonstrate molecular interactions between HCV and L1 elements. HCV infection stably increases cellular levels of the L1-encoded ORF1 protein (L1ORF1p). HCV core and L1ORF1p interact in ribonucleoprotein complexes that traffic to lipid droplets. Despite its redistribution to HCV assembly sites, L1ORF1p is dispensable for HCV infection. In contrast, retrotransposition of engineered L1 reporter elements is restricted by HCV, correlating with an increased formation of L1ORF1p-containing cytoplasmic stress granules. Thus, our data provide first insights into the molecular interplay of endogenous transposable elements and exogenous viruses that might contribute to disease progression in vivo. |
| Databáze: | OpenAIRE |
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