人丙肝病毒的结构生物学研究进展

人丙肝病毒的结构生物学研究进展

徐彩煌，张  兴,张小东，吴永平^*

（1.浙江大学医学院生物物理系，邵逸夫医院病理科,浙江 杭州 310058；2. 浙江农林大学动物科技学院，浙江 临安 311300)

摘  要   丙型肝炎在全球范围内继续传播，每年增加300万新感染病例。丙型肝炎病毒（Hepatitis virus, HCV）属于黄病毒科肝炎病毒属的病毒，被认为是肝硬化和肝细胞癌的主要病因。HCV具有单个正链RNA基因组，其编码由大约3 000个氨基酸组成的多聚蛋白前体。该蛋白在多个位点被切割生成结构蛋白和非结构蛋白。过去几年中，在阐明HCV蛋白质的结构方面取得了很大进展，其中大部分蛋白质可作为抗病毒靶标进行研究。但是，HCV蛋白在病毒生命周期期间执行多种功能，且这些功能可以通过不同的结构构象和/或与病毒和/或细胞蛋白的相互作用进行调节。本文总结了近几年在HCV结构生物学领域的现有知识并介绍该领域的最新进展。

关键词  丙型肝炎病毒；结构生物学；研究进展

中国分类号：R117；R183；R373.9；Q67       文献标识码：A    doi:10.3969/j.issn.1000-6281.2023.01.015

Advances in structural biology of human hepatitis C virus

XÜ Cai-huang ¹，ZHANG Xing ¹，ZHANG Xiao-dong ²，WU Yong-ping ^2*

（1. Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang 310058；2. College of Animal Science and Technology, Zhejiang A&F University, Linan Zhejiang 311300，China ）

Abstract  Hepatitis C has been spreading worldwide, with 3 million new infections each year. Hepatitis C virus (hepatitis virus, HCV) belongs to the genus Hepatitis virus of the Flaviviridae and is considered to be the main cause of cirrhosis and hepatocellular carcinoma. HCV has a single positive-stranded RNA genome encoded by approximately 3000 amino acids. The precursor protein is cleaved at multiple sites to generate structural and non-structural proteins. In the past few years, great progress has been made in elucidating the structure of HCV proteins, most of which are being investigated as antiviral targets. However, HCV proteins respond to multiple functions during the viral life cycle, and these functions can be controlled by different structural conformations and/or interactions with viruses and/or cellular proteins. This paper summarizes the current knowledge in the field of structural biology of HCV in recent years and highlights recent advances in this area.

Keywords   hepatitis C virus; structural biology; research progress

“全文下载请到同方知网，万方数据库或重庆维普等数据库中下载！”

[1] LINDEMBACH B D, RICE C M. The ins and outs of hepatitis C virus entry and assembly [J]. Nature Reviews Microbiology, 2013, 11 (10):688-700.

[2] de CHASSEY B, NAVRATIL V, TAFFOREAU L, et al. Hepatitis C virus infection protein network [J]. Molecular Systems Biology, 2008, 4:230-241.

[3] QUADE N, BOEHRINGER D, LEIBUNDGUT M, et al. Cryo-EM structure of Hepatitis C virus IRES bound to the human ribosome at 3.9-A resolution [J]. Nature Communications, 2015, 6:7646-7654.

[4] JEAN D. Hepatitis C virus proteins [J]. Cell Host Microbe, 2010, 8 (1):77-85.

[5] OEHLER V, FILIPE A, MONTSERRET R, et al. Structural analysis of hepatitis C virus core-E1 signal peptide and requirements for cleavage of the genotype 3a signal sequence by signal peptide peptidase [J]. Journal of Virology, 2012, 86 (15):7818-7828.

[6] KUSHIMA Y, WAKITA T, HIJIKATA M.  A disulfide-bonded dimer of the core protein of hepatitis C virus is important for virus-like particle production [J]. Journal of Virology, 2010,84(18):9118-9127.

[7] BOULANT S, VANBELLE C, EBEL C, et al. Hepatitis C virus core protein is a dimeric alpha-helical protein exhibiting membrane protein features [J]. Journal of Virology, 2005, 79(17) :11353-11365.

[8] CRISTOFARI G, IYANVI-NAGY R, GABUS C，et al. The hepatitis C virus core protein is a potent nucleic acid chaperone that directs dimerization of the viral (+) strand RNA in vitro [J].  Nucleic Acids Research, 2004, 32 (8):2623-2631.

[9] IVANYI-NAGY R, KANEVSKY I, GABUS C, et al. Analysis of hepatitis C virus RNA dimerization and core-RNA interactions [J]. Nucleic Acids Research, 2006, 34(9):2618-2633.

[10] BOSON B, GRANIO O, BARTENSCHLAGER R, et al. A concerted action of hepatitis C virus p7 and nonstructural protein 2 regulates core localization at the endoplasmic reticulum and virus assembly[J]. PLos Pathogens, 2011, 7 (7):e1002144.

[11] CARRERE-KREMER S, MONTPELLIER-PALA C, COCQUEREL L, et al. Subcellular localization and topology of the p7 polypeptide of hepatitis C virus [J].  Journal of Virology, 2002, 76(8):3720-3730.

[12] SCHREGEL V, JACOBI S, PENIN F, et al. Hepatitis C virus NS2 is a protease stimulated by cofactor domains in NS3[J]. Proceedings of the National Academy of Sciences, 2009, 106(13):5342-5347.

[13] JIRASKO V, MONTSERRET R, LEE J Y, et al. Structural and functional studies of nonstructural protein 2 of the hepatitis C virus reveal its key role as organizer of virion assembly [J]. PLos Pathogens, 2010, 6(12):e1001233.

[14] TORRENTS de la PENA A, SLIEPEN K, ESHUN-WILSON L, et al. Structure of the hepatitis C virus E1E2 glycoprotein complex [J]. Science, 2022, 378(6617):263-269.

[15] BERAN R K, LINDENBACH B D, PYLE A M. The NS4A protein of hepatitis C virus promotes RNA-coupled ATP hydrolysis by the NS3 helicase [J]. Journal of Virology, 2009, 83(7):3268-3275.

[16] KIELIAN M, REY F A. Virus membrane-fusion proteins: more than one way to make a hairpin [J]. Nature Reviews Microbiology, 2006, 4(1):67-76.

[17] RANEY K D, SHARMA S D, MOUSTAFA I M, et al. Hepatitis C virus non-structural protein 3 (HCV NS3): a multifunctional antiviral target [J]. Journal of Biological Chemistry, 2010, 285(30):22725-22731.

[18] ALZAHRANI N, WU M J, SOUSA C F, et al. SPCS1-Dependent E2-p7 processing determines HCV assembly efficiency [J]. PLoS Pathogens, 2022, 18(2):e1010310.

[19] LORENZ I C, MARCOTRIGIANO J, DENTZER T G, et al. Structure of the catalytic domain of the hepatitis C virus NS2-3 protease [J]. Nature, 2006, 442 (7104):831-835.

[20] STEINMANN E, PIETSCHMANN T.  Hepatitis C virus p7-a viroporin crucial for virus assembly and an emerging target for antiviral therapy [J]. Viruses, 2010, 2(9):2078-2095.

[21] CHANDLER D E, PENIN F, SCHULTEN K, et al. The p7 protein of hepatitis C virus forms structurally plastic, minimalist ion channels [J]. Plos Computational Biology, 2012, 8(9):e1002702.

[22] LUIK P, CHEW C, AITTONIEMI J, et al. The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy [J]. Proceedings of the National Academy of Sciences, 2009, 106(31):12712-12716.

[23] JONES D M, PATEL A H, TARGETT-ADAMA P, et al.  The hepatitis C virus NS4B protein can trans-complement viral RNA replication and modulates production of infectious virus [J].  Journal of Virology, 2009, 83(5):2163-2177.

[24] TELLINGHUISEN T L, MARCOTRIGIANO J, GORBALENYA A E, et al. The NS5A protein of hepatitis C virus is a zinc metalloprotein [J]. Journal of Biological Chemistry, 2004, 279(47):48576-48587.

[25] MORADPOUR D, BRASS V, PENIN F.  Function follows form: the structure of the N-terminal domain of HCV NS5A [J]. Hepatology, 2005, 42(3):732-735.

[26] YU G Y, LEE K J, GAO L, et al. Palmitoylation and polymerization of hepatitis C virus NS4B protein [J]. Journal of Virology, 2006, 80(12):6013-6023.

[27] GOSERT R, EGGER D, LOHMANN V, et al. Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons [J].  Journal of Virology, 2003,77(9):5487-5492.

[28] YU X, QIAO M, ATANASOV I, et al. Cryo-electron microscopy and three-dimensional reconstructions of hepatitis C virus particles[J]. Virology, 2007, 367(1):126-134.

[29] CATANESE M T, URYU K, KOPP M, et al.  Ultrastructural analysis of hepatitis C virus particles[J]. Proceedings of the National Academy of Sciences, 2013, 110(23):9505-9510.