en
Scientific article
English

Effects of hepatitis C virus on suppressor of cytokine signaling mRNA levels: comparison between different genotypes and core protein sequence analysis

Published inJournal of medical virology, vol. 83, no. 6, p. 1005-1015
Publication date2011
Abstract

Glucose metabolism disturbances, including insulin resistance and type 2 diabetes, are frequent and important cofactors of hepatitis C. Increasing epidemiological and experimental data suggest that all major genotypes of hepatitis C virus (HCV), albeit to a different extent, cause insulin resistance. The HCV core protein has been shown to be sufficient to impair insulin signaling in vitro through several post-receptorial mechanisms, mostly via the activation of suppressor of cytokine signaling (SOCS) family members and the consequent decrease of insulin receptor substrate-1 (IRS-1). The levels of IRS-1 and SOCS were investigated upon expression of the core protein of HCV genotypes 1-4. Furthermore, the core protein sequences were analyzed to identify the amino acid residues responsible for IRS-1 decrease, with particular regard to SOCS mRNA deregulation. The results suggest that the activation of SOCS family members is a general mechanism associated with the common HCV genotypes. A rare genotype 1b variant, however, failed to activate any of the SOCS tested: this allowed to analyze in detail the distinct amino acid sequences responsible for SOCS deregulation. By combining approaches using intergenotypic chimeras and site-directed mutagenesis, genetic evidence was provided in favor of a role of amino acids 49 and 131 of the HCV core-encoding sequence in mediating SOCS transactivation.

Keywords
  • Amino Acid Sequence
  • Cell Line
  • Diabetes Mellitus, Type 2/complications
  • Genotype
  • Hepacivirus/classification/genetics/physiology
  • Hepatitis C/complications/metabolism
  • Humans
  • Insulin Receptor Substrate Proteins/genetics/metabolism
  • Insulin Resistance/physiology
  • Mutagenesis, Site-Directed
  • RNA, Messenger/genetics/metabolism
  • Recombinant Fusion Proteins
  • Sequence Alignment
  • Signal Transduction/genetics
  • Suppressor of Cytokine Signaling Proteins/genetics/metabolism
  • Transcriptional Activation/genetics
  • Viral Core Proteins/chemistry/genetics/metabolism
  • Virus Replication
Citation (ISO format)
PASCARELLA ROCHAT, Stéphanie et al. Effects of hepatitis C virus on suppressor of cytokine signaling mRNA levels: comparison between different genotypes and core protein sequence analysis. In: Journal of medical virology, 2011, vol. 83, n° 6, p. 1005–1015. doi: 10.1002/jmv.22072
Main files (1)
Article (Published version)
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Identifiers
ISSN of the journal0146-6615
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