Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon-gamma stimuli.
We established hepatitis C virus (HCV) core-expressing cells and investigated whether HCV core would modify the Janus kinase (JAK)-signal transducer and activator transcription factor (STAT) pathway under interleukin-6 (IL-6) and interferon (IFN)-gamma stimuli. Phosphorylation of JAK1/2 and STAT3, and STAT3-mediated transcription, were prevented by HCV core under IL-6 stimulation. In contrast, HCV core increased phosphorylation of JAK1/2 and STAT1 and STAT1-mediated transcription under IFN-gamma stimulation. Immunoprecipitation/Western blot analysis showed that HCV core could bind to JAK1/2. The PGYPWP sequences at codons 79-84 within HCV core were important for interaction with JAKs by in vitro binding analysis. In the reporter gene assay, HCV core-mediated suppression of JAK-STAT pathway under IL-6 stimulation was not observed by abrogation of PGYPWP sequence, suggesting that HCV core/JAK interaction may directly affect the signal transduction. In contrast, augmentation of JAK-STAT pathway was still seen by HCV core without functional PGYPWP sequence under IFN-gamma stimulation. Flow cytometric analysis revealed that HCV core up-regulated of IFN-gamma receptor 2 expression, which may be responsible for HCV core-mediated enhancement of JAK-STAT pathway under IFN-gamma stimulation. In conclusion, HCV core has different effects on the JAK-STAT pathway under IL-6 and IFN-gamma stimuli. This may be exerted by these two independent mechanisms.
Hosui
Atsushi
A
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Ohkawa
Kazuyoshi
K
Ishida
Hisashi
H
Sato
Aki
A
Nakanishi
Fumihiko
F
Ueda
Keiji
K
Takehara
Tetsuo
T
Kasahara
Akinori
A
Sasaki
Yutaka
Y
Hori
Masatsugu
M
Hayashi
Norio
N
D000818:Animals; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008099:Liver; D008113:Liver Neoplasms; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D015850:Interleukin-6; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D014758:Viral Core Proteins; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse