Glycometabolism regulates hepatitis C virus release

doi:10.1371/journal.ppat.1009746

	Glycometabolism regulates hepatitis C virus release
	Yu, Tao 1,2; Yang, Qiankun 1,2; Tian, Fangling1,2,3 ; Chang, Haishuang 4; Hu, Zhenzheng 4; Yu, Bowen 4; Han, Lin1,2,3 ; Xing, Yifan 1,2,5; Jiu, Yaming 4,5; He, Yongning 4,6; Zhong, Jin1,2,3
	2021-07
发表期刊	PLOS PATHOGENS (IF:5.5[JCR-2023],5.5[5-Year])
ISSN	1553-7366
EISSN	1553-7374
卷号	17 期号:7
DOI	10.1371/journal.ppat.1009746
摘要	Author summary Hepatitis C virus (HCV) is a positive-stranded RNA virus that causes acute and chronic hepatitis and hepatocellular carcinoma. HCV infectious cycle comprises viral entry, uncoating, translation and replication of viral RNA, assembly into new virions and release. Establishment of HCV cell culture system (HCVcc) has yielded many insights into complete HCV infectious cycle in Huh7 cell and Huh7-derived human hepatoma cell lines. However, because hepatoma-derived cell lines and hepatocytes vary in metabolism, HCV infectious cycle in tumor cell lines and the patient's liver may also be different. Therefore, we explored the alterations of HCV infectious cycle by forcing the tumor cell lines to switch their glycometabolic pathways. We found that HCV release can be blocked by culturing cells in galactose-containing medium, leading to accumulation of intracellular infectious virions within MVB. Moreover, we provided new evidence to suggest that HCV cell-to-cell transmission may be mechanistically distinct from cell-to-supernatant release. Finally, we proposed a new concept that HCV release from hepatocytes into circulation may be naturally inefficient due to the metabolic state in liver that may favor more HCV cell-to-cell transmission. This strategy would allow HCV to effectively evade neutralizing antibodies to establish persistent infection. HCV cell-culture system uses hepatoma-derived cell lines for efficient virus propagation. Tumor cells cultured in glucose undergo active aerobic glycolysis, but switch to oxidative phosphorylation for energy production when cultured in galactose. Here, we investigated whether modulation of glycolysis in hepatocytes affects HCV infection. We showed HCV release, but not entry, genome replication or virion assembly, is significantly blocked when cells are cultured in galactose, leading to accumulation of intracellular infectious virions within multivesicular body (MVB). Blockade of the MVB-lysosome fusion or treatment with pro-inflammatory cytokines promotes HCV release in galactose. Furthermore, we found this glycometabolic regulation of HCV release is mediated by MAPK-p38 phosphorylation. Finally, we showed HCV cell-to-cell transmission is not affected by glycometabolism, suggesting that HCV cell-to-supernatant release and cell-to-cell transmission are two mechanistically distinct pathways. In summary, we demonstrated glycometabolism regulates the efficiency and route of HCV release. We proposed HCV may exploit the metabolic state in hepatocytes to favor its spread through the cell-to-cell transmission in vivo to evade immune response.
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收录类别	SCIE
语种	英语
WOS研究方向	Microbiology ; Parasitology ; Virology
WOS类目	Microbiology ; Parasitology ; Virology
WOS记录号	WOS:000677729700004
出版者	PUBLIC LIBRARY SCIENCE
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/127865
专题	生命科学与技术学院_特聘教授组_钟劲组生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Zhong, Jin
作者单位	1.Chinese Acad Sci, Inst Pasteur Shanghai, Unit Viral Hepatitis, CAS Key Lab Mol Virol & Immunol, Shanghai, Peoples R China; 2.Univ Chinese Acad Sci, Beijing, Peoples R China; 3.ShanghaiTech Univ, Shanghai, Peoples R China; 4.Chinese Acad Sci, Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, Shanghai, Peoples R China; 5.Chinese Acad Sci, Inst Pasteur Shanghai, Cell Biol & Imaging Study Pathogen Host Interact, CAS Key Lab Mol Virol & Immunol, Shanghai, Peoples R China; 6.Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Sch Med, Shanghai, Peoples R China
通讯作者单位	上海科技大学
推荐引用方式 GB/T 7714	Yu, Tao,Yang, Qiankun,Tian, Fangling,et al. Glycometabolism regulates hepatitis C virus release[J]. PLOS PATHOGENS,2021,17(7).
APA	Yu, Tao.,Yang, Qiankun.,Tian, Fangling.,Chang, Haishuang.,Hu, Zhenzheng.,...&Zhong, Jin.(2021).Glycometabolism regulates hepatitis C virus release.PLOS PATHOGENS,17(7).
MLA	Yu, Tao,et al."Glycometabolism regulates hepatitis C virus release".PLOS PATHOGENS 17.7(2021).