Upregulation of protein phosphatase 2Ac by hepatitis C virus modulates NS3 helicase activity through inhibition of protein arginine methyltransferase 1

Détails

ID Serval
serval:BIB_DDC8ADFA2C39
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Upregulation of protein phosphatase 2Ac by hepatitis C virus modulates NS3 helicase activity through inhibition of protein arginine methyltransferase 1
Périodique
Journal of Virology
Auteur(s)
Duong  F. H., Christen  V., Berke  J. M., Penna  S. H., Moradpour  D., Heim  M. H.
ISSN
0022-538X (Print)
Statut éditorial
Publié
Date de publication
12/2005
Volume
79
Numéro
24
Pages
15342-50
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Dec
Résumé
Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. HCV has a positive-strand RNA genome of about 9.4 kb in size, which serves as a template for replication and for translation of a polyprotein of about 3,000 amino acids. The polyprotein is cleaved co- and posttranslationally by cellular and viral proteases into at least 10 different mature proteins. One of these proteins, nonstructural protein 3 (NS3), has serine protease and NTPase/RNA helicase activity. Arginine 467 in the helicase domain of NS3 (arginine 1493 in the polyprotein) can be methylated by protein arginine methyltransferase 1 (PRMT1). Here we report that the methylation of NS3 inhibits the enzymatic activity of the helicase. Furthermore, we found that PRMT1 activity itself is regulated by protein phosphatase 2A (PP2A). PP2A inhibits PRMT1 enzymatic activity and therefore increases the helicase activity of NS3. This is important, because we found an increased expression of PP2A in cell lines with inducible HCV protein expression, in transgenic mice expressing HCV proteins in hepatocytes, and in liver biopsy samples from patients with chronic hepatitis C. Interestingly, up-regulation of PP2A not only modulates the enzymatic activity of an important viral protein, NS3 helicase, but also interferes with the cellular defense against viruses by inhibiting interferon-induced signaling through signal transducer and activator of transcription 1 (STAT1). We conclude that up-regulation of PP2A might be crucial for the efficient replication of HCV and propose PP2A as a potential target for anti-HCV treatment strategies.
Mots-clé
Cell Line Hepacivirus/chemistry/*physiology Humans Phosphoprotein Phosphatase/*metabolism Protein-Arginine N-Methyltransferase/*antagonists & inhibitors/metabolism RNA Helicases/chemistry/*metabolism Up-Regulation Viral Nonstructural Proteins/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/01/2008 17:06
Dernière modification de la notice
20/08/2019 17:02
Données d'usage