Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication
| Autor: | Geoffrey J. Clark, Daniel Brian Nichols, Diego F. Calvisi, Neerja Kaushik-Basu, Howard Donninger, M. Lee Schmidt, Amartya Basu, Payal Arora |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Carcinoma Hepatocellular Hepatitis C virus Hepacivirus Down-Regulation Viral Nonstructural Proteins Virus Replication medicine.disease_cause Article law.invention 03 medical and health sciences chemistry.chemical_compound law medicine Humans NS5B Adaptor Proteins Signal Transducing Monomeric GTP-Binding Proteins Hepatology biology Liver Neoplasms virus diseases biology.organism_classification medicine.disease Virology digestive system diseases Cell biology NS2-3 protease HEK293 Cells 030104 developmental biology Liver chemistry Viral replication Suppressor Signal transduction Apoptosis Regulatory Proteins Liver cancer |
| Zdroj: | Hepatology. 65:1462-1477 |
| ISSN: | 1527-3350 0270-9139 |
| Popis: | Hepatitis C virus (HCV) infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here, we show that the HCV protein, nonstructural protein (NS) 5B, directly binds to the tumor suppressor, NORE1A (RASSF5), and promotes its proteosomal degradation. In addition, we show that NORE1A colocalizes to sites of HCV viral replication and suppresses the replication process. Thus, NORE1A has antiviral activity, which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples. Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and may make a major contribution to HCV-induced liver cancer by shifting Ras signaling away from prosenescent/proapoptotic signaling pathways. CONCLUSION HCV uses NS5B to specifically suppress NORE1A, facilitating viral replication and elevated Ras signaling. (Hepatology 2017;65:1462-1477). |
| Databáze: | OpenAIRE |
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