title: HCV core protein binds to gC1qR to induce A20 expression and inhibit cytokine production through MAPKs and NF-κB signaling pathways.
abstract: Hepatitis C virus (HCV) infection is characterized by a strong propensity toward chronicity. During chronic HCV infection, HCV core protein is implicated in deregulating cytokine expression that associates with chronic inflammation. A20 is known as a powerful suppressor in cytokine signaling, in this study, we explored the A20 expression in macrophages induced by HCV core protein and the involved signaling pathways. Results demonstrated that HCV core protein induced A20 expression in macrophages. Silencing A20 significantly enhanced the secretion of IL-6, IL-1β and TGF-β1, but not IL-8 and TNF. Additionally, HCV core protein interacted with gC1qR, but not TLR2, TLR3 and TLR4 in pull-down assay. Silencing gC1qR abrogated core-induced A20 expression. Furthermore, HCV core protein activated MAPK, NF-κB and PI3K/AKT pathways in macrophages. Inhibition of P38, JNK and NF-κB but not ERK and AKT activities greatly reduced the A20 expression. In conclusion, the study suggests that HCV core protein ligates gC1qR to induce A20 expression in macrophages via P38, JNK and NF-κB signaling pathways, which leads to a low-grade chronic inflammation during HCV infection. It represents a novel mechanism by which HCV usurps the host for persistence.
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Jianling
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Zhengzheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Cuiqing
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Li
authors.affiliation: Division of Infectious Diseases, Allergy and Immunology, Departments of Internal Medicine and Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Immunology, Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D016174:Hepacivirus / Q000276:immunology / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics / Q000378:metabolism*; D014758:Viral Core Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: C087299:C1QBP protein, human; C490193:C1qbp protein, mouse; D002352:Carrier Proteins; D016207:Cytokines; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D014758:Viral Core Proteins; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C513261:Tnfaip3 protein, mouse
keywords: Immune response; Immunity; Immunology and Microbiology Section; core protein; gC1qR; hepatitis C virus; macrophage; negative regulator A20