Hepatitis C Virus (HCV) Induces Formation of Stress Granules Whose Proteins Regulate HCV RNA Replication and Virus Assembly and Egress
| Autor: | Bryan Boyd, Urtzi Garaigorta, Stefan Wieland, Markus H. Heim, Francis V. Chisari |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Myxovirus Resistance Proteins
Hepacivirus Virus Replication Small hairpin RNA eIF-2 Kinase Interferon RNA interference RNA Small Interfering Poly-ADP-Ribose Binding Proteins Virus Release 0303 health sciences 030302 biochemistry & molecular biology RNA-Binding Proteins Virus-Cell Interactions 3. Good health RNA Recognition Motif Proteins RNA Viral RNA Interference Ubiquitin Thiolesterase RNA Helicases medicine.drug Immunology Down-Regulation Biology Cytoplasmic Granules Poly(A)-Binding Proteins Microbiology Virus Cell Line 03 medical and health sciences Stress granule GTP-Binding Proteins Cell Line Tumor Virology Endopeptidases medicine Humans RNA Messenger 030304 developmental biology Virus Assembly DNA Helicases RNA Interferon-beta T-Cell Intracellular Antigen-1 NS2-3 protease HEK293 Cells Protein Biosynthesis Insect Science Carrier Proteins |
| Zdroj: | Journal of virology |
| ISSN: | 1098-5514 0022-538X |
| Popis: | Stress granules (SGs) are cytoplasmic structures that are induced in response to environmental stress, including viral infections. Here we report that hepatitis C virus (HCV) triggers the appearance of SGs in a PKR- and interferon (IFN)-dependent manner. Moreover, we show an inverse correlation between the presence of stress granules and the induction of IFN-stimulated proteins, i.e., MxA and USP18, in HCV-infected cells despite high-level expression of the corresponding MxA and USP18 mRNAs, suggesting that interferon-stimulated gene translation is inhibited in stress granule-containing HCV-infected cells. Finally, in short hairpin RNA (shRNA) knockdown experiments, we found that the stress granule proteins T-cell-restricted intracellular antigen 1 (TIA-1), TIA1-related protein (TIAR), and RasGAP-SH3 domain binding protein 1 (G3BP1) are required for efficient HCV RNA and protein accumulation at early time points in the infection and that G3BP1 and TIA-1 are required for intracellular and extracellular infectious virus production late in the infection, suggesting that they are required for virus assembly. In contrast, TIAR downregulation decreases extracellular infectious virus titers with little effect on intracellular RNA content or infectivity late in the infection, suggesting that it is required for infectious particle release. Collectively, these results illustrate that HCV exploits the stress granule machinery at least two ways: by inducing the formation of SGs by triggering PKR phosphorylation, thereby downregulating the translation of antiviral interferon-stimulated genes, and by co-opting SG proteins for its replication, assembly, and egress. |
| Databáze: | OpenAIRE |
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