title: The hepatitis C virus core protein modulates T cell responses by inducing spontaneous and altering T-cell receptor-triggered Ca2+ oscillations.
abstract: Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infection, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Expression of the HCV core (C) protein modulates transcription of the IL-2 promoter in T lymphocytes by activating the nuclear factor of activated T lymphocyte (NFAT) pathway. Here we report on the effect of HCV C on Ca2+ signaling, which is essential for activation of NFAT. Expression of HCV C correlated with increased levels of cytosolic Ca2+ and spontaneous Ca2+ oscillations in transfected Jurkat cells. Triggering of the T-cell receptor induced a prolonged Ca2+ response characterized by vigorous high frequent oscillations in a high proportion of the responding cells. This was associated with decreased sizes and accelerated emptying of the intracellular calcium stores. The effect of HCV C on calcium mobilization was not dependent on phospholipase C-gamma 1 (PLC-gamma) activity or increased inositol 1,4,5-trisphosphate (IP3) production and did not require functional IP3 receptors, suggesting that insertion of the viral protein in the endoplasmic reticulum membrane may be sufficient to promote Ca2+ leakage with dramatic downstream consequences on the magnitude and duration of the response. Our data suggest that expression of HCV C in infected T lymphocytes may contribute to the establishment of persistent infections by inducing Ca2+ oscillations that regulate both the efficacy and information content of Ca2+ signals and are ultimately responsible for induction of gene expression and functional differentiation.
authors.affiliation: Microbiology and Tumor Biology Centre, Karolinska Institutet, SE-17177 Stockholm, Sweden. anders.bergqvist@mtc.ki.se
authors.forename: Anders
authors.initials: A
authors.lastname: Bergqvist
authors.forename: Sara
authors.initials: S
authors.lastname: Sundström
authors.forename: Lina Y
authors.initials: LY
authors.lastname: Dimberg
authors.forename: Erik
authors.initials: E
authors.lastname: Gylfe
authors.forename: Maria G
authors.initials: MG
authors.lastname: Masucci
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression; D016174:Hepacivirus / Q000737:chemistry*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019169:Jurkat Cells; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D051966:Phospholipase C gamma; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D004268:DNA-Binding Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium