一项功能基因组筛选鉴定出丙型肝炎病毒复制的细胞辅助因子。
A functional genomic screen identifies cellular cofactors of hepatitis C virus replication.
作者信息
Tai Andrew W, Benita Yair, Peng Lee F, Kim Sun-Suk, Sakamoto Naoya, Xavier Ramnik J, Chung Raymond T
机构信息
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
出版信息
Cell Host Microbe. 2009 Mar 19;5(3):298-307. doi: 10.1016/j.chom.2009.02.001.
Abstract
Hepatitis C virus (HCV) chronically infects 3% of the world's population, and complications from HCV are the leading indication for liver transplantation. Given the need for better anti-HCV therapies, one strategy is to identify and target cellular cofactors of the virus lifecycle. Using a genome-wide siRNA library, we identified 96 human genes that support HCV replication, with a significant number of them being involved in vesicle organization and biogenesis. Phosphatidylinositol 4-kinase PI4KA and multiple subunits of the COPI vesicle coat complex were among the genes identified. Consistent with this, pharmacologic inhibitors of COPI and PI4KA blocked HCV replication. Targeting hepcidin, a peptide critical for iron homeostasis, also affected HCV replication, which may explain the known dysregulation of iron homeostasis in HCV infection. The host cofactors for HCV replication identified in this study should serve as a useful resource in delineating new targets for anti-HCV therapies.
摘要
丙型肝炎病毒（HCV）长期感染全球3%的人口，HCV引发的并发症是肝移植的主要指征。鉴于需要更好的抗HCV疗法，一种策略是识别并靶向病毒生命周期的细胞辅助因子。利用全基因组siRNA文库，我们鉴定出96个人类基因可支持HCV复制，其中大量基因参与囊泡组织和生物发生。磷脂酰肌醇4激酶PI4KA和COPI囊泡包被复合体的多个亚基都在鉴定出的基因之中。与此一致的是，COPI和PI4KA的药理抑制剂可阻断HCV复制。靶向铁调素（一种对铁稳态至关重要的肽）也会影响HCV复制，这可能解释了HCV感染中铁稳态已知的失调情况。本研究中鉴定出的HCV复制宿主辅助因子应可作为描绘抗HCV疗法新靶点的有用资源。
相似文献
1
A functional genomic screen identifies cellular cofactors of hepatitis C virus replication.一项功能基因组筛选鉴定出丙型肝炎病毒复制的细胞辅助因子。
Cell Host Microbe. 2009 Mar 19;5(3):298-307. doi: 10.1016/j.chom.2009.02.001.
2
Identification of a lipid kinase as a host factor involved in hepatitis C virus RNA replication.鉴定一种脂质激酶作为参与丙型肝炎病毒RNA复制的宿主因子。
Virology. 2009 Apr 25;387(1):5-10. doi: 10.1016/j.virol.2009.02.039. Epub 2009 Mar 21.
3
Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment.丙型肝炎病毒 NS5A 通过招募和激活一种脂质激酶对于膜复制隔间的完整性是必需的。
Cell Host Microbe. 2011 Jan 20;9(1):32-45. doi: 10.1016/j.chom.2010.12.002.
4
Hepatitis C virus stimulates the phosphatidylinositol 4-kinase III alpha-dependent phosphatidylinositol 4-phosphate production that is essential for its replication.丙型肝炎病毒刺激磷脂酰肌醇 4-激酶 IIIα 依赖性的磷脂酰肌醇 4-磷酸产生，这对其复制是必需的。
J Virol. 2011 Sep;85(17):8870-83. doi: 10.1128/JVI.00059-11. Epub 2011 Jun 22.
5
Roles for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in hepatitis C virus replication.内吞运输和磷脂酰肌醇4激酶IIIα在丙型肝炎病毒复制中的作用。
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7577-82. doi: 10.1073/pnas.0902693106. Epub 2009 Apr 17.
6
Mapping of functional domains of the lipid kinase phosphatidylinositol 4-kinase type III alpha involved in enzymatic activity and hepatitis C virus replication.参与酶活性和丙型肝炎病毒复制的脂质激酶III型α-磷脂酰肌醇4激酶功能域的定位
J Virol. 2014 Sep 1;88(17):9909-26. doi: 10.1128/JVI.01063-14. Epub 2014 Jun 11.
7
Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides.达卡他韦可抑制丙型肝炎病毒NS5A的运动性及磷酸肌醇的过度积累。
Virology. 2015 Feb;476:168-179. doi: 10.1016/j.virol.2014.12.018. Epub 2014 Dec 26.
8
Modulation of hepatitis C virus replication by iron and hepcidin in Huh7 hepatocytes.铁和铁调素对 Huh7 肝细胞中丙型肝炎病毒复制的调控。
J Gen Virol. 2011 Sep;92(Pt 9):2072-2081. doi: 10.1099/vir.0.032706-0. Epub 2011 May 18.
9
PI4K-beta and MKNK1 are regulators of hepatitis C virus IRES-dependent translation.PI4K-β和MKNK1是丙型肝炎病毒内部核糖体进入位点（IRES）依赖性翻译的调节因子。
Sci Rep. 2015 Sep 1;5:13344. doi: 10.1038/srep13344.
10
Integrative functional genomics of hepatitis C virus infection identifies host dependencies in complete viral replication cycle.丙型肝炎病毒感染的整合功能基因组学确定了病毒完整复制周期中的宿主依赖性。
PLoS Pathog. 2014 May 22;10(5):e1004163. doi: 10.1371/journal.ppat.1004163. eCollection 2014 May.
引用本文的文献
1
Plant negative-strand RNA virus phosphoprotein condensates exploit host trafficking and lipid synthesis for viral factory assembly.植物负链RNA病毒磷蛋白凝聚物利用宿主运输和脂质合成来组装病毒工厂。
Sci Adv. 2025 Aug 22;11(34):eadx7905. doi: 10.1126/sciadv.adx7905. Epub 2025 Aug 20.
2
Phosphatidylinositol 4-phosphate; A minor lipid with multiple personalities.磷脂酰肌醇4-磷酸：一种具有多种特性的次要脂质。
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jun;1870(5):159615. doi: 10.1016/j.bbalip.2025.159615. Epub 2025 Apr 20.
3
Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products.连接代谢组和表型：功能代谢组学工具在鉴定生物活性天然产物方面的最新进展。
Nat Prod Rep. 2024 Jun 19;41(6):885-904. doi: 10.1039/d3np00050h.
4
Sex and Age Impact CD4+ T Cell Susceptibility to HIV In Vitro through Cell Activation Dynamics.性别和年龄通过细胞激活动力学影响 HIV 体外感染 CD4+T 细胞的易感性。
Cells. 2023 Nov 23;12(23):2689. doi: 10.3390/cells12232689.
5
Hepatitis C virus alters the morphology and function of peroxisomes.丙型肝炎病毒会改变过氧化物酶体的形态和功能。
Front Microbiol. 2023 Sep 21;14:1254728. doi: 10.3389/fmicb.2023.1254728. eCollection 2023.
6
A disintegrin and metalloproteinase domain 9 facilitates SARS-CoV-2 entry into cells with low ACE2 expression.解整合素金属蛋白酶9促进严重急性呼吸综合征冠状病毒2进入血管紧张素转换酶2表达低的细胞。
Microbiol Spectr. 2023 Sep 15;11(5):e0385422. doi: 10.1128/spectrum.03854-22.
7
PEMT Mediates Hepatitis C Virus-Induced Steatosis, Explains Genotype-Specific Phenotypes and Supports Virus Replication.PEMT 介导丙型肝炎病毒诱导的脂肪变性，解释基因型特异性表型并支持病毒复制。
Int J Mol Sci. 2023 May 15;24(10):8781. doi: 10.3390/ijms24108781.
8
Essential Domains of Oxysterol-Binding Protein Required for Poliovirus Replication.必需的氧化固醇结合蛋白结构域对于脊髓灰质炎病毒复制的作用。
Viruses. 2022 Nov 29;14(12):2672. doi: 10.3390/v14122672.
9
WTAP Targets the METTL3 mA-Methyltransferase Complex to Cytoplasmic Hepatitis C Virus RNA to Regulate Infection.WTAP 靶向 METTL3 mA-甲基转移酶复合物到细胞质丙型肝炎病毒 RNA 以调节感染。
J Virol. 2022 Nov 23;96(22):e0099722. doi: 10.1128/jvi.00997-22. Epub 2022 Oct 31.
10
A Proteomic Approach to Study the Biological Role of Hepatitis C Virus Protein Core+1/ARFP.应用蛋白质组学方法研究丙型肝炎病毒核心蛋白+1/ARFP 的生物学作用
Viruses. 2022 Jul 31;14(8):1694. doi: 10.3390/v14081694.
本文引用的文献
1
Genome-scale RNAi screen for host factors required for HIV replication.针对HIV复制所需宿主因子的全基因组RNA干扰筛选。
Cell Host Microbe. 2008 Nov 13;4(5):495-504. doi: 10.1016/j.chom.2008.10.004. Epub 2008 Oct 30.
2
Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication.对调节早期HIV-1复制的宿主-病原体相互作用的全局分析。
Cell. 2008 Oct 3;135(1):49-60. doi: 10.1016/j.cell.2008.07.032.
3
The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus.亲环蛋白抑制剂Debio-025在丙型肝炎和人类免疫缺陷病毒合并感染患者中显示出强效的抗丙型肝炎作用。
Hepatology. 2008 Mar;47(3):817-26. doi: 10.1002/hep.22131.
4
Identification of host proteins required for HIV infection through a functional genomic screen.通过功能基因组筛选鉴定HIV感染所需的宿主蛋白。
Science. 2008 Feb 15;319(5865):921-6. doi: 10.1126/science.1152725. Epub 2008 Jan 10.
5
Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion.丙型肝炎病毒组装、成熟、降解及分泌的细胞决定因素。
J Virol. 2008 Mar;82(5):2120-9. doi: 10.1128/JVI.02053-07. Epub 2007 Dec 12.
6
Identification of human kinases involved in hepatitis C virus replication by small interference RNA library screening.通过小干扰RNA文库筛选鉴定参与丙型肝炎病毒复制的人类激酶
J Biol Chem. 2008 Jan 4;283(1):29-36. doi: 10.1074/jbc.M703988200. Epub 2007 Oct 19.
7
DDX3 DEAD-box RNA helicase is required for hepatitis C virus RNA replication.丙型肝炎病毒RNA复制需要DDX3 DEAD盒RNA解旋酶。
J Virol. 2007 Dec;81(24):13922-6. doi: 10.1128/JVI.01517-07. Epub 2007 Sep 12.
8
A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2.神经元特异性钾氯共转运体KCC2的一种新型N端异构体。
J Biol Chem. 2007 Oct 19;282(42):30570-6. doi: 10.1074/jbc.M705095200. Epub 2007 Aug 22.
9
Cellular cofactors affecting hepatitis C virus infection and replication.影响丙型肝炎病毒感染与复制的细胞辅助因子
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12884-9. doi: 10.1073/pnas.0704894104. Epub 2007 Jul 6.
10
Identification of host genes involved in hepatitis C virus replication by small interfering RNA technology.利用小干扰RNA技术鉴定丙型肝炎病毒复制相关的宿主基因。
Hepatology. 2007 Jun;45(6):1413-21. doi: 10.1002/hep.21608.
Zotero 插件