Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein.
Hepatitis B virus (HBV) X protein (HBx) is a key factor for regulating viral transcription and replication. We recently characterized homeobox protein MSX-1 (MSX1) as a host restriction factor that inhibits HBV gene expression and genome replication by directly binding to HBV enhancer II/core promot...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-01-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012897 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832540361314009088 |
|---|---|
| author | Qian Qiu Zihan He Jing Liu Huijun Xu Jinyu Wang Nannan Liu Ning Kang Shaokun Pan Weien Yu Zixiang Gao Shimei Zhang Yang Yang Qiang Deng Youhua Xie Jiming Zhang Zhongliang Shen |
| author_facet | Qian Qiu Zihan He Jing Liu Huijun Xu Jinyu Wang Nannan Liu Ning Kang Shaokun Pan Weien Yu Zixiang Gao Shimei Zhang Yang Yang Qiang Deng Youhua Xie Jiming Zhang Zhongliang Shen |
| author_sort | Qian Qiu |
| collection | DOAJ |
| description | Hepatitis B virus (HBV) X protein (HBx) is a key factor for regulating viral transcription and replication. We recently characterized homeobox protein MSX-1 (MSX1) as a host restriction factor that inhibits HBV gene expression and genome replication by directly binding to HBV enhancer II/core promoter (EnII/Cp) and suppressing its promoter and enhancer activities. Notably, HBx expression was observed to be repressed more drastically by MSX1 compared to other viral antigens. In this work, we report that in addition to transcriptional repression, MSX1 also post-transcriptionally downregulates HBx protein stability. Mechanistically, MSX1 induces ubiquitin-independent proteasomal degradation of HBx, which is mediated through HBx C-terminal domain. Furthermore, this effect on HBx degradation correlates with MSX1-induced upregulation of DNAJA4 and CRYAB expression. Similar to MSX1, both DNAJA4 and CRYAB promote HBx degradation and repress HBV gene expression and genome replication. In chronic hepatitis B (CHB) patients, immune active phase (IA) is associated with higher intrahepatic expression of MSX1, DNAJA4 and CRYAB, and lower serum HBV markers compared to immune tolerant (IT) phase. Finally, HBV infection is significantly suppressed by MSX1 overexpression in both NTCP-overexpressing cell and humanized liver mouse models. These results demonstrate additional and novel mechanisms of MSX1-mediated repression of HBV, and establish MSX1 as a multi-functional HBV restriction factor with therapeutic potential. |
| format | Article |
| id | doaj-art-f335970ec61e44a99041bb6a2e2c76e8 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-f335970ec61e44a99041bb6a2e2c76e82025-02-05T05:30:52ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-01-01211e101289710.1371/journal.ppat.1012897Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein.Qian QiuZihan HeJing LiuHuijun XuJinyu WangNannan LiuNing KangShaokun PanWeien YuZixiang GaoShimei ZhangYang YangQiang DengYouhua XieJiming ZhangZhongliang ShenHepatitis B virus (HBV) X protein (HBx) is a key factor for regulating viral transcription and replication. We recently characterized homeobox protein MSX-1 (MSX1) as a host restriction factor that inhibits HBV gene expression and genome replication by directly binding to HBV enhancer II/core promoter (EnII/Cp) and suppressing its promoter and enhancer activities. Notably, HBx expression was observed to be repressed more drastically by MSX1 compared to other viral antigens. In this work, we report that in addition to transcriptional repression, MSX1 also post-transcriptionally downregulates HBx protein stability. Mechanistically, MSX1 induces ubiquitin-independent proteasomal degradation of HBx, which is mediated through HBx C-terminal domain. Furthermore, this effect on HBx degradation correlates with MSX1-induced upregulation of DNAJA4 and CRYAB expression. Similar to MSX1, both DNAJA4 and CRYAB promote HBx degradation and repress HBV gene expression and genome replication. In chronic hepatitis B (CHB) patients, immune active phase (IA) is associated with higher intrahepatic expression of MSX1, DNAJA4 and CRYAB, and lower serum HBV markers compared to immune tolerant (IT) phase. Finally, HBV infection is significantly suppressed by MSX1 overexpression in both NTCP-overexpressing cell and humanized liver mouse models. These results demonstrate additional and novel mechanisms of MSX1-mediated repression of HBV, and establish MSX1 as a multi-functional HBV restriction factor with therapeutic potential.https://doi.org/10.1371/journal.ppat.1012897 |
| spellingShingle | Qian Qiu Zihan He Jing Liu Huijun Xu Jinyu Wang Nannan Liu Ning Kang Shaokun Pan Weien Yu Zixiang Gao Shimei Zhang Yang Yang Qiang Deng Youhua Xie Jiming Zhang Zhongliang Shen Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein. PLoS Pathogens |
| title | Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein. |
| title_full | Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein. |
| title_fullStr | Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein. |
| title_full_unstemmed | Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein. |
| title_short | Homeobox protein MSX-1 restricts hepatitis B virus by promoting ubiquitin-independent proteasomal degradation of HBx protein. |
| title_sort | homeobox protein msx 1 restricts hepatitis b virus by promoting ubiquitin independent proteasomal degradation of hbx protein |
| url | https://doi.org/10.1371/journal.ppat.1012897 |
| work_keys_str_mv | AT qianqiu homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT zihanhe homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT jingliu homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT huijunxu homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT jinyuwang homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT nannanliu homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT ningkang homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT shaokunpan homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT weienyu homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT zixianggao homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT shimeizhang homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT yangyang homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT qiangdeng homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT youhuaxie homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT jimingzhang homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein AT zhongliangshen homeoboxproteinmsx1restrictshepatitisbvirusbypromotingubiquitinindependentproteasomaldegradationofhbxprotein |