Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation

被引:74
|
作者
Anggakusuma [1 ]
Romero-Brey, Ines [2 ]
Berger, Carola [2 ]
Colpitts, Che C. [3 ,4 ,5 ]
Boldanova, Tujana [6 ,7 ]
Engelmann, Michael [1 ]
Todt, Daniel [1 ]
Perin, Paula Monteiro [1 ]
Behrendt, Patrick [1 ,8 ]
Vondran, Florian W. R. [9 ,10 ]
Xu, Shuting [1 ]
Goffinet, Christine [1 ]
Schang, Luis M. [3 ,4 ,5 ]
Heim, Markus H. [6 ,7 ]
Bartenschlager, Ralf [2 ,11 ]
Pietschmann, Thomas [1 ]
Steinmann, Eike [1 ]
机构
[1] Twincore Ctr Expt & Clin Infect Res, Inst Expt Virol, D-30625 Hannover, Germany
[2] Heidelberg Univ, Dept Infect Dis, Mol Virol, Heidelberg, Germany
[3] Univ Alberta, Dept Biochem, Edmonton, AB, Canada
[4] Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB, Canada
[5] Univ Alberta, Li Ka Shing Inst Virol, Edmonton, AB, Canada
[6] Univ Basel, Dept Biomed, Basel, Switzerland
[7] Univ Basel Hosp, Div Gastroenterol & Hepatol, CH-4031 Basel, Switzerland
[8] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany
[9] Hannover Med Sch, Dept Gen Visceral & Transplantat Surg, ReMediES, Hannover, Germany
[10] German Ctr Infect Res, Hannover, Germany
[11] Heidelberg Univ, German Ctr Infect Res, Heidelberg, Germany
关键词
OXYSTEROL-BINDING-PROTEIN; CHOLESTEROL; 25-HYDROXYLASE; RNA REPLICATION; ANTIVIRAL RESPONSE; IMMUNE-RESPONSES; INNATE IMMUNITY; MX PROTEINS; 25-HYDROXYCHOLESTEROL; ACTIVATION; INFECTION;
D O I
10.1002/hep.27913
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Hepatitis C virus (HCV) is a positive-strand RNA virus that primarily infects human hepatocytes. Infections with HCV constitute a global health problem, with 180 million people currently chronically infected. Recent studies have reported that cholesterol 25-hydroxylase (CH25H) is expressed as an interferon-stimulated gene and mediates antiviral activities against different enveloped viruses through the production of 25-hydroxycholesterol (25HC). However, the intrinsic regulation of human CH25H (hCH25H) expression within the liver as well as its mechanistic effects on HCV infectivity remain elusive. In this study, we characterized the expression of hCH25H using liver biopsies and primary human hepatocytes. In addition, the antiviral properties of this protein and its enzymatic product, 25HC, were further characterized against HCV in tissue culture. Levels of hCH25H messenger RNA were significantly up-regulated both in HCV-positive liver biopsies and in HCV-infected primary human hepatocytes. The expression of hCH25H in primary human hepatocytes was primarily and transiently induced by type I interferon. Transient expression of hCH25H in human hepatoma cells restricted HCV infection in a genotype-independent manner. This inhibition required the enzymatic activity of CH25H. We observed an inhibition of viral membrane fusion during the entry process by 25HC, which was not due to a virucidal effect. Yet the primary effect by 25HC on HCV was at the level of RNA replication, which was observed using subgenomic replicons of two different genotypes. Further analysis using electron microscopy revealed that 25HC inhibited formation of the membranous web, the HCV replication factory, independent of RNA replication. Conclusion: Infection with HCV causes up-regulation of interferon-inducible CH25H in vivo, and its product, 25HC, restricts HCV primarily at the level of RNA replication by preventing formation of the viral replication factory. (Hepatology 2015;62:702-714)
引用
收藏
页码:702 / 714
页数:13
相关论文
共 50 条
  • [1] Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication via blockage of membranous web formation
    Kusuma, A.
    Romero-Brey, I.
    Berger, C.
    Colpitts, C. C.
    Boldanova, T.
    Todt, D.
    Perin, P. M.
    Behrendt, P.
    Vondran, F. W. R.
    Xu, S.
    Goffinet, C.
    Schang, L. M.
    Heim, M. H.
    Bartenschlager, R.
    Pietschmann, T.
    Steinmann, E.
    JOURNAL OF VIRAL HEPATITIS, 2015, 22 : 69 - 69
  • [2] Interferon-Inducible Cholesterol-25-Hydroxylase Inhibits Hepatitis C Virus Replication via Distinct Mechanisms
    Chen, Yongzhi
    Wang, Shanshan
    Yi, Zhaohong
    Tian, Huabin
    Aliyari, Roghiyh
    Li, Yanhua
    Chen, Gang
    Liu, Ping
    Zhong, Jin
    Chen, Xinwen
    Du, Peishuang
    Su, Lishan
    Qin, F. Xiao-Feng
    Deng, Hongyu
    Cheng, Genhong
    SCIENTIFIC REPORTS, 2014, 4
  • [3] Interferon-Inducible Cholesterol-25-Hydroxylase Inhibits Hepatitis C Virus Replication via Distinct Mechanisms
    Yongzhi Chen
    Shanshan Wang
    Zhaohong Yi
    Huabin Tian
    Roghiyh Aliyari
    Yanhua Li
    Gang Chen
    Ping Liu
    Jin Zhong
    Xinwen Chen
    Peishuang Du
    Lishan Su
    F. Xiao-Feng Qin
    Hongyu Deng
    Genhong Cheng
    Scientific Reports, 4
  • [4] Interferon-Inducible Cholesterol-25-Hydroxylase Broadly Inhibits Viral Entry by Production of 25-Hydroxycholesterol
    Liu, Su-Yang
    Aliyari, Roghiyh
    Chikere, Kelechi
    Li, Guangming
    Marsden, Matthew D.
    Smith, Jennifer K.
    Pernet, Olivier
    Guo, Haitao
    Nusbaum, Rebecca
    Zack, Jerome A.
    Freiberg, Alexander N.
    Su, Lishan
    Lee, Benhur
    Cheng, Genhong
    IMMUNITY, 2013, 38 (01) : 92 - 105
  • [5] Dual-Role of Cholesterol-25-Hydroxylase in Regulating Hepatitis B Virus Infection and Replication
    Wei, Qi
    Song, Hongxiao
    Gao, Yanli
    Xu, Fengchao
    Xiao, Qingfei
    Wang, Fei
    Lei, Bingxin
    Niu, Junqi
    Gao, Pujun
    Ma, Haichun
    Tan, Guangyun
    MBIO, 2022, 13 (03):
  • [6] Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus
    Jiang, Dong
    Guo, Haitao
    Xu, Chunxiao
    Chang, Jinhong
    Gu, Baohua
    Wang, Lijuan
    Block, Timothy M.
    Guo, Ju-Tao
    JOURNAL OF VIROLOGY, 2008, 82 (04) : 1665 - 1678
  • [7] 25-Hydroxycholesterol Production by the Cholesterol-25-Hydroxylase Interferon-Stimulated Gene Restricts Mammalian Reovirus Infection
    Doms, Alexandra
    Sanabria, Tatiana
    Hansen, Jeanne N.
    Altan-Bonnet, Nihal
    Holm, Geoffrey H.
    JOURNAL OF VIROLOGY, 2018, 92 (18)
  • [8] Inhibition of hepatitis B virus replication by the interferon-inducible MxA protein
    Gordien, E
    Rosmorduc, O
    Peltekian, C
    Garreau, F
    Bréchot, C
    Kremsdorf, D
    JOURNAL OF VIROLOGY, 2001, 75 (06) : 2684 - 2691
  • [9] Interferon-Inducible GTPase 1 Impedes the Dimerization of Rabies Virus Phosphoprotein and Restricts Viral Replication
    Tian, Bin
    Yuan, Yueming
    Yang, Yu
    Luo, Zhaochen
    Sui, Baokun
    Zhou, Ming
    Fu, Zhen F.
    Zhao, Ling
    JOURNAL OF VIROLOGY, 2020, 94 (21)
  • [10] Interferon-inducible SAMHD1 restricts viral replication through downregulation of lipid synthesis
    An, Ni
    Ge, Qinghua
    Shao, Huihan
    Li, Quanjie
    Guo, Fei
    Liang, Chen
    Li, Xiaoyu
    Yi, Dongrong
    Yang, Long
    Cen, Shan
    FRONTIERS IN IMMUNOLOGY, 2022, 13