Rapamycin inhibits hepatitis B virus covalently closed circular DNA transcription by enhancing the ubiquitination of HBx

作者全名："Zhang, Yuan; Li, Liang; Cheng, Sheng-Tao; Qin, Yi-Ping; He, Xin; Li, Fan; Wu, Dai-Qing; Ren, Fang; Yu, Hai-Bo; Liu, Jing; Chen, Juan; Ren, Ji-Hua; Zhang, Zhen-Zhen"

作者地址："[Zhang, Yuan; Cheng, Sheng-Tao; Qin, Yi-Ping; He, Xin; Wu, Dai-Qing; Yu, Hai-Bo; Liu, Jing; Chen, Juan; Ren, Ji-Hua] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Chinese Minist Educ, Chongqing, Peoples R China; [Zhang, Yuan; Zhang, Zhen-Zhen] Chongqing Med Univ, Dept Infect Dis, Childrens Hosp, Chongqing, Peoples R China; [Zhang, Yuan; Zhang, Zhen-Zhen] Minist Educ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Chongqing, Peoples R China; [Zhang, Yuan; Zhang, Zhen-Zhen] Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China; [Li, Liang] Chongqing Univ Three Gorges Hosp, Dept Gastroenterol, Chongqing, Peoples R China; [Li, Fan] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing, Peoples R China; [Ren, Fang] Chongqing Key Lab Sichuan Chongqing Coconstruct Di, Chongqing, Peoples R China; [Ren, Fang] Chongqing Hosp Tradit Chinese Med, Dept Lab Med, Chongqing, Peoples R China"

通信作者："Ren, JH (通讯作者)，Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Chinese Minist Educ, Chongqing, Peoples R China.; Zhang, ZZ (通讯作者)，Chongqing Med Univ, Dept Infect Dis, Childrens Hosp, Chongqing, Peoples R China.; Zhang, ZZ (通讯作者)，Minist Educ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Chongqing, Peoples R China.; Zhang, ZZ (通讯作者)，Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China."

来源：FRONTIERS IN MICROBIOLOGY

ESI学科分类：MICROBIOLOGY

WOS号：WOS:000891372700001

JCR分区：Q2

影响因子：5.2

年份：2022

卷号：13

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：rapamycin; hepatitis B virus; HBx; covalently closed circular DNA; transcription

摘要："Hepatitis B virus (HBV) infection is still a serious public health problem worldwide. Antiviral therapies such as interferon and nucleos(t)ide analogs efficiently control HBV replication, but they cannot eradicate chronic hepatitis B (CHB) because of their incapacity to eliminate endocellular covalently closed circular DNA (cccDNA). Thus, there is a necessity to develop new strategies for targeting cccDNA. As cccDNA is difficult to clear, transcriptional silencing of cccDNA is a possible effective strategy. HBx plays a vitally important role in maintaining the transcriptional activity of cccDNA and it could be a target for blocking the transcription of cccDNA. To screen new drugs that may contribute to antiviral therapy, the ability of 2,000 small-molecule compounds to inhibit HBx was examined by the HiBiT lytic detection system. We found that the macrolide compound rapamycin, which is clinically used to prevent acute rejection after organ transplantation, could significantly reduce HBx protein expression. Mechanistic studies demonstrated that rapamycin decreased the stability of the HBx protein by promoting its degradation via the ubiquitin-proteasome system. Moreover, rapamycin inhibited HBV RNA, HBV DNA, and cccDNA transcription levels in HBV-infected cells. In addition, HBx deficiency abrogated the inhibition of cccDNA transcription induced by rapamycin. Similar results were also confirmed in a recombinant cccDNA mouse model. In summary, we report a new small-molecule, rapamycin, which targets HBx to block HBV cccDNA transcription and inhibit HBV replication. This approach can identify new strategies to cure CHB."

基金机构：National Natural Science Foundation of China; Natural Science Foundation Project of Chongqing; Chongqing Talents Project; Scientific and Technological Research Program of Chongqing Municipal Education Commission; College Young Teachers Fund of the Fok Ying Tung Education Foundation; [81871656]; [81922011]; [cstc2019jscx-dxwtBX0020]; [cstc2021ycjh-bgzxm0121]; [KJQN202100429]; [171100]

基金资助正文："Funding This work was supported by the National Natural Science Foundation of China (Grant Nos. 81871656 and 81922011 to JC), the Natural Science Foundation Project of Chongqing (Grant No. cstc2019jscx-dxwtBX0020 to JC), the Chongqing Talents Project (Grant No. cstc2021ycjh-bgzxm0121 to JC), the Scientific and Technological Research Program of Chongqing Municipal Education Commission (Grant No. KJQN202100429 to J-HR), and the College Young Teachers Fund of the Fok Ying Tung Education Foundation (Grant No. 171100 to J-HR)."