title: Effects of hepatitis C virus on suppressor of cytokine signaling mRNA levels: comparison between different genotypes and core protein sequence analysis.
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.
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pascarella
authors.forename: Sophie
authors.initials: S
authors.lastname: Clément
authors.forename: Kévin
authors.initials: K
authors.lastname: Guilloux
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Conzelmann
authors.forename: François
authors.initials: F
authors.lastname: Penin
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000150:complications / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014758:Viral Core Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D050826:Suppressor of Cytokine Signaling Proteins; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus