HCV RNA 依赖性 RNA 聚合酶在肝脏中的表达会触发先天免疫信号和细胞因子的产生。
Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production.
机构信息
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0723, USA.
出版信息
Mol Cell. 2012 Oct 26;48(2):313-21. doi: 10.1016/j.molcel.2012.07.032. Epub 2012 Sep 6.
Abstract
Innate immunity controls pathogen replication and spread. Yet, certain pathogens, such as Hepatitis C Virus (HCV), escape immune elimination and establish persistent infections that promote chronic inflammation and related diseases. Whereas HCV regulatory proteins that attenuate antiviral responses are known, those that promote inflammation and liver injury remain to be identified. Here, we show that transient expression of HCV RNA-dependent RNA polymerase (RdRp), NS5B, in mouse liver and human hepatocytes results in production of small RNA species that activate innate immune signaling via TBK1-IRF3 and NF-κB and induce cytokine production, including type I interferons (IFN) and IL-6. NS5B-expression also results in liver damage.
摘要
先天免疫控制病原体的复制和传播。然而，某些病原体，如丙型肝炎病毒 (HCV)，逃脱了免疫清除，建立了持续性感染，从而促进慢性炎症和相关疾病。虽然已经知道 HCV 调节蛋白会减弱抗病毒反应，但那些促进炎症和肝损伤的蛋白仍有待确定。在这里，我们表明 HCV RNA 依赖性 RNA 聚合酶 (RdRp)、NS5B 的瞬时表达会导致小鼠肝脏和人肝细胞中产生小 RNA 种类，这些小 RNA 种类通过 TBK1-IRF3 和 NF-κB 激活先天免疫信号，并诱导细胞因子的产生，包括 I 型干扰素 (IFN) 和 IL-6。NS5B 的表达也会导致肝损伤。
相似文献
1
Hepatic expression of HCV RNA-dependent RNA polymerase triggers innate immune signaling and cytokine production.
Mol Cell. 2012 Oct 26;48(2):313-21. doi: 10.1016/j.molcel.2012.07.032. Epub 2012 Sep 6.
2
HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons.
Gastroenterology. 2012 Apr;142(4):978-88. doi: 10.1053/j.gastro.2011.12.055. Epub 2012 Jan 13.
3
Hepatitis C virus NS3/4A protease blocks IL-28 production.
Eur J Immunol. 2012 Sep;42(9):2374-82. doi: 10.1002/eji.201242388.
4
Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity.
J Hepatol. 2013 Jul;59(1):52-8. doi: 10.1016/j.jhep.2013.03.019. Epub 2013 Mar 28.
5
Hepatitis C Virus Infection Is Inhibited by a Noncanonical Antiviral Signaling Pathway Targeted by NS3-NS4A.
J Virol. 2019 Nov 13;93(23). doi: 10.1128/JVI.00725-19. Print 2019 Dec 1.
6
The Molecular Chaperone GRP78 Contributes to Toll-like Receptor 3-mediated Innate Immune Response to Hepatitis C Virus in Hepatocytes.
J Biol Chem. 2016 Jun 3;291(23):12294-309. doi: 10.1074/jbc.M115.711598. Epub 2016 Apr 20.
7
Transcriptional regulation of IFN-λ genes in hepatitis C virus-infected hepatocytes via IRF-3·IRF-7·NF-κB complex.
J Biol Chem. 2014 Feb 21;289(8):5310-9. doi: 10.1074/jbc.M113.536102. Epub 2014 Jan 2.
8
Ribonucleotide reductase M2 promotes RNA replication of hepatitis C virus by protecting NS5B protein from hPLIC1-dependent proteasomal degradation.
J Biol Chem. 2019 Apr 12;294(15):5759-5773. doi: 10.1074/jbc.RA118.004397. Epub 2019 Feb 12.
9
Lymphotoxin signaling is initiated by the viral polymerase in HCV-linked tumorigenesis.
PLoS Pathog. 2013 Mar;9(3):e1003234. doi: 10.1371/journal.ppat.1003234. Epub 2013 Mar 21.
10
Interference of HCV replication by cell penetrable human monoclonal scFv specific to NS5B polymerase.
MAbs. 2014;6(5):1327-39. doi: 10.4161/mabs.29978.
引用本文的文献
1
Effect of C-type lectin 16 on dengue virus infection in salivary glands.
PNAS Nexus. 2024 May 16;3(5):pgae188. doi: 10.1093/pnasnexus/pgae188. eCollection 2024 May.
2
Celastrol attenuates hepatitis C virus translation and inflammatory response in mice by suppressing heat shock protein 90β.
Acta Pharmacol Sin. 2023 Aug;44(8):1637-1648. doi: 10.1038/s41401-023-01067-w. Epub 2023 Mar 7.
3
HCV and tumor-initiating stem-like cells.
Front Physiol. 2022 Sep 15;13:903302. doi: 10.3389/fphys.2022.903302. eCollection 2022.
4
Nonstructural Proteins: The Role in Molecular Mechanisms of Triggering Inflammation.
Viruses. 2022 Aug 18;14(8):1808. doi: 10.3390/v14081808.
5
Prognostic utility of systemic inflammatory markers and chronic hepatitis C virus infection status in hepatocellular carcinoma patients treated with local ablation.
BMC Cancer. 2022 Feb 28;22(1):221. doi: 10.1186/s12885-021-09121-8.
6
Activation of the STAT3 Signaling Pathway by the RNA-Dependent RNA Polymerase Protein of Arenavirus.
Viruses. 2021 May 25;13(6):976. doi: 10.3390/v13060976.
7
Aggressive organ penetration and high vector transmissibility of epidemic dengue virus-2 Cosmopolitan genotype in a transmission mouse model.
PLoS Pathog. 2021 Mar 30;17(3):e1009480. doi: 10.1371/journal.ppat.1009480. eCollection 2021 Mar.
8
Hepatocellular carcinoma after direct-acting antiviral hepatitis C virus therapy: A debate near the end.
World J Gastroenterol. 2020 Nov 21;26(43):6770-6781. doi: 10.3748/wjg.v26.i43.6770.
9
Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis.
Viruses. 2020 Jun 11;12(6):635. doi: 10.3390/v12060635.
10
Genetically Modified Mouse Mesenchymal Stem Cells Expressing Non-Structural Proteins of Hepatitis C Virus Induce Effective Immune Response.
Vaccines (Basel). 2020 Feb 2;8(1):62. doi: 10.3390/vaccines8010062.
本文引用的文献
1
TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2.
Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):E177-86. doi: 10.1073/pnas.1119296109. Epub 2011 Dec 27.
2
Inflammation meets cancer, with NF-κB as the matchmaker.
Nat Immunol. 2011 Jul 19;12(8):715-23. doi: 10.1038/ni.2060.
3
Pattern recognition receptors and inflammation.
Cell. 2010 Mar 19;140(6):805-20. doi: 10.1016/j.cell.2010.01.022.
4
RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway.
Cell. 2009 Aug 7;138(3):576-91. doi: 10.1016/j.cell.2009.06.015. Epub 2009 Jul 23.
5
Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences.
Int J Cancer. 2009 Nov 15;125(10):2264-9. doi: 10.1002/ijc.24720.
6
Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA.
Nature. 2008 Jul 24;454(7203):523-7. doi: 10.1038/nature07106. Epub 2008 Jun 11.
7
Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.
Science. 2007 Jul 6;317(5834):121-4. doi: 10.1126/science.1140485.
8
Flying under the radar: the immunobiology of hepatitis C.
Annu Rev Immunol. 2007;25:71-99. doi: 10.1146/annurev.immunol.25.022106.141602.
9
Hepatitis C virus NS5B delays cell cycle progression by inducing interferon-beta via Toll-like receptor 3 signaling pathway without replicating viral genomes.
Virology. 2006 Mar 15;346(2):348-62. doi: 10.1016/j.virol.2005.10.023. Epub 2005 Dec 2.
10
Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.
Nature. 2006 Jan 12;439(7073):204-7. doi: 10.1038/nature04369. Epub 2005 Nov 23.
Zotero 插件