Osteopontin Regulates Hepatitis C Virus (HCV) Replication and Assembly by Interacting with HCV Proteins and Lipid Droplets and by Binding to Receptors αVβ3 and CD44
| العنوان: | Osteopontin Regulates Hepatitis C Virus (HCV) Replication and Assembly by Interacting with HCV Proteins and Lipid Droplets and by Binding to Receptors αVβ3 and CD44 |
|---|---|
| المؤلفون: | Binod Kumar, Jawed Iqbal, Mehuli Sarkar-Dutta, Gulam Waris, Akshaya Ramachandran, Steven McRae |
| المصدر: | Journal of Virology. 92 |
| بيانات النشر: | American Society for Microbiology, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | DNA Replication, 0301 basic medicine, Small interfering RNA, Carcinoma, Hepatocellular, Immunology, Integrin, Hepacivirus, Viral Nonstructural Proteins, Biology, Virus Replication, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, stomatognathic system, Virology, Lipid droplet, Tumor Cells, Cultured, Humans, Osteopontin, NS5A, Receptor, NS5B, Virus Assembly, Liver Neoplasms, virus diseases, Lipid Droplets, Transfection, Integrin alphaVbeta3, Hepatitis C, digestive system diseases, Virus-Cell Interactions, Cell biology, Hyaluronan Receptors, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Insect Science, biology.protein, RNA, Viral |
| الوصف: | Hepatitis C virus (HCV) replication and assembly occur at the specialized site of endoplasmic reticulum (ER) membranes and lipid droplets (LDs), respectively. Recently, several host proteins have been shown to be involved in HCV replication and assembly. In the present study, we demonstrated the important relationship among osteopontin (OPN), the ER, and LDs. OPN is a secreted phosphoprotein, and overexpression of OPN in hepatocellular carcinoma (HCC) tissue can lead to invasion and metastasis. OPN expression is also enhanced in HCV-associated HCC. Our recent studies have demonstrated the induction, proteolytic cleavage, and secretion of OPN in response to HCV infection. We also defined the critical role of secreted OPN in human hepatoma cell migration and invasion through binding to receptors integrin αVβ3 and CD44. However, the role of HCV-induced OPN in the HCV life cycle has not been elucidated. In this study, we showed a significant reduction in HCV replication, assembly, and infectivity in HCV-infected cells transfected with small interfering RNA (siRNA) against OPN, αVβ3, and CD44. We also observed the association of endogenous OPN with HCV proteins (NS3, NS5A, NS4A/B, NS5B, and core). Confocal microscopy revealed the colocalization of OPN with HCV NS5A and core in the ER and LDs, indicating a possible role for OPN in HCV replication and assembly. Interestingly, the secreted OPN activated HCV replication, infectivity, and assembly through binding to αVβ3 and CD44. Collectively, these observations provide evidence that HCV-induced OPN is critical for HCV replication and assembly. IMPORTANCE Recently, our studies uncovered the critical role of HCV-induced endogenous and secreted OPN in migration and invasion of hepatocytes. However, the role of OPN in the HCV life cycle has not been elucidated. In this study, we investigated the importance of OPN in HCV replication and assembly. We demonstrated that endogenous OPN associates with HCV NS3, NS5A, NS5B, and core proteins, which are in close proximity to the ER and LDs. Moreover, we showed that the interactions of secreted OPN with cell surface receptors αVβ3 and CD44 are critical for HCV replication and assembly. These observations provide evidence that HCV-induced endogenous and secreted OPN play pivotal roles in HCV replication and assembly in HCV-infected cells. Taken together, our findings clearly demonstrate that targeting OPN may provide opportunities for therapeutic intervention of HCV pathogenesis. |
| تدمد: | 1098-5514 0022-538X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::065fa7599457071d5d12f9401d0ba9baTest https://doi.org/10.1128/jvi.02116-17Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....065fa7599457071d5d12f9401d0ba9ba |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10985514 0022538X |
|---|