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

Conzelmann, Stéphanie
Penin, François
Published in Journal of medical virology. 2011, vol. 83, no. 6, p. 1005-15
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 SequenceCell LineDiabetes Mellitus, Type 2/complicationsGenotypeHepacivirus/classification/genetics/physiologyHepatitis C/complications/metabolismHumansInsulin Receptor Substrate Proteins/genetics/metabolismInsulin Resistance/physiologyMutagenesis, Site-DirectedRNA, Messenger/genetics/metabolismRecombinant Fusion ProteinsSequence AlignmentSignal Transduction/geneticsSuppressor of Cytokine Signaling Proteins/genetics/metabolismTranscriptional Activation/geneticsViral Core Proteins/chemistry/genetics/metabolismVirus Replication
PMID: 21503913
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Research group Etudes et traitement de l'hépatite C et B (554)
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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. 1005-15. doi: 10.1002/jmv.22072 https://archive-ouverte.unige.ch/unige:24269

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Deposited on : 2012-11-30

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