Hepatitis C virus proteins interfere with the activation of chemokine gene promoters and downregulate chemokine gene expression.
The hepatitis C virus (HCV) non-structural (NS) 3/4A protein complex inhibits the retinoic acid inducible gene I (RIG-I) pathway by proteolytically cleaving mitochondria-associated CARD-containing adaptor protein Cardif, and this leads to reduced production of beta interferon (IFN-beta). This study examined the expression of CCL5 (regulated upon activation, normal T-cell expressed and secreted, or RANTES), CXCL8 (interleukin 8) and CXCL10 (IFN-gamma-activated protein 10, or IP-10) chemokine genes in osteosarcoma cell lines that inducibly expressed NS3/4A, NS4B, core-E1-E2-p7 and the entire HCV polyprotein. Sendai virus (SeV)-induced production of IFN-beta, CCL5, CXCL8 and CXCL10 was downregulated by the NS3/4A protein complex and by the full-length HCV polyprotein. Expression of NS3/4A and the HCV polyprotein reduced the binding of interferon regulatory factors (IRFs) 1 and 3 and, to a lesser extent, nuclear factor (NF)-kappaB (p65/p50) to their respective binding elements on the CXCL10 promoter during SeV infection. Furthermore, binding of IRF1 and IRF3 to the interferon-stimulated response element-like element, and of c-Jun and phosphorylated c-Jun to the activator protein 1 element of the CXCL8 promoter, was reduced when NS3/4A and the HCV polyprotein were expressed. In cell lines expressing NS3/4A and the HCV polyprotein, the subcellular localization of mitochondria was changed, and this was kinetically associated with the partial degradation of endogenous Cardif. These results indicate that NS3/4A alone or as part of the HCV polyprotein disturbs the expression of IRF1- and IRF3-regulated genes, as well as affecting mitogen-activated protein kinase kinase- and NF-kappaB-regulated genes.
Sillanpää
Maarit
M
Department of Viral Diseases and Immunology, National Public Health Institute, FIN-00300 Helsinki, Finland.
Kaukinen
Pasi
P
Department of Viral Diseases and Immunology, National Public Health Institute, FIN-00300 Helsinki, Finland.
Melén
Krister
K
Department of Viral Diseases and Immunology, National Public Health Institute, FIN-00300 Helsinki, Finland.
Julkunen
Ilkka
I
Department of Viral Diseases and Immunology, National Public Health Institute, FIN-00300 Helsinki, Finland.
D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016174:Hepacivirus / Q000737:chemistry* / Q000235:genetics; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D008928:Mitochondria / Q000502:physiology; D020815:Polyproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D018925:Chemokines; D020815:Polyproteins; D017361:Viral Nonstructural Proteins; C097010:NS2 protein, Hepatitis C virus; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases