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Manganese is a potent inducer of lysosomal activity that inhibits de novo HBV infection

文献类型：期刊论文

作者Yu, Lin2,3; Chang, Hao2,3; Xie, Wentao2,3,4; Zheng, Yuan2,3; Yang, Le2,3; Wu, Qiong2,3; Bu, Fan2,3; Zhu, Yuanfei2,3; Xie, Youhua2,3; Pan, Guoyu5
刊名PLOS PATHOGENS
出版日期2025
卷号21期号:1页码:31
ISSN号1553-7366
DOI10.1371/journal.ppat.1012800
通讯作者Pan, Guoyu(gypan@simm.ac.cn) ; Lan, Ke(klan@whu.edu.cn) ; Deng, Qiang(qdeng@fudan.edu.cn)
英文摘要Sodium taurocholate co-transporting polypeptide (NTCP) has been identified as an entry receptor for hepatitis B virus (HBV), but the molecular events of the viral post-endocytosis steps remain obscure. In this study, we discovered that manganese (Mn) could strongly inhibit HBV infection in NTCP-reconstituted HepG2 cells without affecting viral replication. We therefore profiled the antiviral effects of Mn2+ in an attempt to elucidate the regulatory mechanisms involved in early HBV infection. Intriguingly, Mn2+ conspicuously stimulated lysosomal activity, as evidenced by hyperactivation of mTORC1 and increased endo/lysosomal acidity. After HBV-triggered internalization, the NTCP receptor was sorted to late endosomal compartments by the ESCRT machinery in concert with the invading virion. The establishment of HBV infection was found to be independent of lysosomal fusion-driven late endosome maturation; Mn2+-induced lysosomal hyperfunction virtually impaired infection, suggesting that virions may gain cytosolic access directly from late endosomes. In contrast, suppression of lysosomal activity substantially enhanced HBV infection. Prolonged mTORC1 inactivation facilitated viral infection by depleting lysosomes and accelerating endocytic transport of virions. Notably, treatment with the natural steroidal alkaloid tomatidine recapitulated the effects of Mn2+ in stimulating lysosomal activity and exhibited potent anti-HBV activity in HepG2-NTCP cells and in proliferating human hepatocyte organoids. These findings provide new insights into the post-endocytosis events of HBV infection. The negative regulation of early HBV infection by endo/lysosomal activity makes it a promising target for antiviral therapies.
WOS关键词HEPATITIS-B-VIRUS ; ENDOSOME MATURATION ; RAG GTPASES ; HEPATOCYTES ; AUTOPHAGY ; PATHWAY ; FUSION ; MTORC1 ; ENTRY ; DNA
资助项目Shanghai Municipal Science and Technology Major Project[ZD2021CY001] ; National Natural Science Foundation grants of China[82072279] ; National Natural Science Foundation grants of China[82372233] ; National Natural Science Foundation grants of China[81871647] ; Innovation Fund for Medical Sciences from Chinese Academy of Medical Sciences[2019-I2M- 5-040]
WOS研究方向Microbiology ; Parasitology ; Virology
语种英语
WOS记录号WOS:001388350700001
出版者PUBLIC LIBRARY SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/315300]  
专题中国科学院上海药物研究所
通讯作者Pan, Guoyu; Lan, Ke; Deng, Qiang
作者单位1.Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan, Peoples R China
2.Fudan Univ, Shanghai Inst Infect Dis & Biosecur, Sch Basic Med Sci, Key Lab Med Mol Virol MOE NHC CAMS, Shanghai, Peoples R China
3.Fudan Univ, Shanghai Frontiers Sci Ctr Pathogen Microorganisms, Shanghai, Peoples R China
4.Huashan Hosp, Natl Med Ctr Infect Dis, Dept Infect Dis, Shanghai Key Lab Infect Dis & Biosafety Emergency, Shanghai, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Yu, Lin,Chang, Hao,Xie, Wentao,et al. Manganese is a potent inducer of lysosomal activity that inhibits de novo HBV infection[J]. PLOS PATHOGENS,2025,21(1):31.
APA Yu, Lin.,Chang, Hao.,Xie, Wentao.,Zheng, Yuan.,Yang, Le.,...&Deng, Qiang.(2025).Manganese is a potent inducer of lysosomal activity that inhibits de novo HBV infection.PLOS PATHOGENS,21(1),31.
MLA Yu, Lin,et al."Manganese is a potent inducer of lysosomal activity that inhibits de novo HBV infection".PLOS PATHOGENS 21.1(2025):31.

入库方式： OAI收割

来源：上海药物研究所

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