Hepatitis C Virus Induces the Ubiquitin-Editing Enzyme A20 via Depletion of the Transcription Factor Upstream Stimulatory Factor 1 To Support Its Replication
ABSTRACT Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), also known as A20, is a ubiquitin-editing enzyme capable of ubiquitination or deubiquitination of its target proteins. In this study, we show that hepatitis C virus (HCV) infection could induce the expression of A20 via the activation...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2019-08-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01660-19 |
| _version_ | 1818843781949030400 |
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| author | Jiyoung Lee Stephanie T. Chan Ja Yeon Kim Jing-hsiung James Ou |
| author_facet | Jiyoung Lee Stephanie T. Chan Ja Yeon Kim Jing-hsiung James Ou |
| author_sort | Jiyoung Lee |
| collection | DOAJ |
| description | ABSTRACT Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), also known as A20, is a ubiquitin-editing enzyme capable of ubiquitination or deubiquitination of its target proteins. In this study, we show that hepatitis C virus (HCV) infection could induce the expression of A20 via the activation of the A20 promoter. The induction of A20 by HCV coincided with the loss of upstream stimulatory factor 1 (USF-1), a transcription factor known to suppress the A20 promoter. The role of USF-1 in the regulation of the A20 promoter in HCV-infected cells was confirmed by the chromatin immunoprecipitation (ChIP) assay, and its depletion was apparently mediated by proteasomes, as USF-1 could be stabilized by the proteasome inhibitor MG132 to suppress the A20 expression. As the overexpression of A20 enhanced the replication of HCV and the silencing of A20 had the opposite effect, A20 is a positive regulator of HCV replication. Our further studies indicated that A20 enhanced the activity of the HCV internal ribosome entry site (IRES). In conclusion, our results demonstrated that HCV could induce the expression of A20 via the depletion of USF-1 to enhance its replication. Our study provided important information for further understanding the interaction between HCV and its host cells. IMPORTANCE Hepatitis C virus establishes chronic infection in approximately 85% of the patients whom it infects. However, the mechanism of how HCV evades host immunity to establish persistence is unclear. In this report, we demonstrate that HCV could induce the expression of the ubiquitin-editing enzyme A20, an important negative regulator of the tumor necrosis factor alpha (TNF-α) and NF-κB signaling pathways. This induction of A20 enhanced HCV replication as it could stimulate the HCV IRES activity to enhance the translation of HCV proteins. The induction of A20 was mediated by the depletion of USF-1, a suppressor of the A20 promoter. Our study thus provides important information for further understanding the interaction between HCV and its host cells. |
| first_indexed | 2024-12-19T05:03:20Z |
| format | Article |
| id | doaj.art-d19569ec2aac405293518e7c64a0e84a |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T05:03:20Z |
| publishDate | 2019-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-d19569ec2aac405293518e7c64a0e84a2022-12-21T20:35:01ZengAmerican Society for MicrobiologymBio2150-75112019-08-0110410.1128/mBio.01660-19Hepatitis C Virus Induces the Ubiquitin-Editing Enzyme A20 via Depletion of the Transcription Factor Upstream Stimulatory Factor 1 To Support Its ReplicationJiyoung Lee0Stephanie T. Chan1Ja Yeon Kim2Jing-hsiung James Ou3Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USAABSTRACT Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), also known as A20, is a ubiquitin-editing enzyme capable of ubiquitination or deubiquitination of its target proteins. In this study, we show that hepatitis C virus (HCV) infection could induce the expression of A20 via the activation of the A20 promoter. The induction of A20 by HCV coincided with the loss of upstream stimulatory factor 1 (USF-1), a transcription factor known to suppress the A20 promoter. The role of USF-1 in the regulation of the A20 promoter in HCV-infected cells was confirmed by the chromatin immunoprecipitation (ChIP) assay, and its depletion was apparently mediated by proteasomes, as USF-1 could be stabilized by the proteasome inhibitor MG132 to suppress the A20 expression. As the overexpression of A20 enhanced the replication of HCV and the silencing of A20 had the opposite effect, A20 is a positive regulator of HCV replication. Our further studies indicated that A20 enhanced the activity of the HCV internal ribosome entry site (IRES). In conclusion, our results demonstrated that HCV could induce the expression of A20 via the depletion of USF-1 to enhance its replication. Our study provided important information for further understanding the interaction between HCV and its host cells. IMPORTANCE Hepatitis C virus establishes chronic infection in approximately 85% of the patients whom it infects. However, the mechanism of how HCV evades host immunity to establish persistence is unclear. In this report, we demonstrate that HCV could induce the expression of the ubiquitin-editing enzyme A20, an important negative regulator of the tumor necrosis factor alpha (TNF-α) and NF-κB signaling pathways. This induction of A20 enhanced HCV replication as it could stimulate the HCV IRES activity to enhance the translation of HCV proteins. The induction of A20 was mediated by the depletion of USF-1, a suppressor of the A20 promoter. Our study thus provides important information for further understanding the interaction between HCV and its host cells.https://journals.asm.org/doi/10.1128/mBio.01660-19A20 ubiquitin enzymeHCV IRESUSF-1 transcription factorhepatitis C virus |
| spellingShingle | Jiyoung Lee Stephanie T. Chan Ja Yeon Kim Jing-hsiung James Ou Hepatitis C Virus Induces the Ubiquitin-Editing Enzyme A20 via Depletion of the Transcription Factor Upstream Stimulatory Factor 1 To Support Its Replication mBio A20 ubiquitin enzyme HCV IRES USF-1 transcription factor hepatitis C virus |
| title | Hepatitis C Virus Induces the Ubiquitin-Editing Enzyme A20 via Depletion of the Transcription Factor Upstream Stimulatory Factor 1 To Support Its Replication |
| title_full | Hepatitis C Virus Induces the Ubiquitin-Editing Enzyme A20 via Depletion of the Transcription Factor Upstream Stimulatory Factor 1 To Support Its Replication |
| title_fullStr | Hepatitis C Virus Induces the Ubiquitin-Editing Enzyme A20 via Depletion of the Transcription Factor Upstream Stimulatory Factor 1 To Support Its Replication |
| title_full_unstemmed | Hepatitis C Virus Induces the Ubiquitin-Editing Enzyme A20 via Depletion of the Transcription Factor Upstream Stimulatory Factor 1 To Support Its Replication |
| title_short | Hepatitis C Virus Induces the Ubiquitin-Editing Enzyme A20 via Depletion of the Transcription Factor Upstream Stimulatory Factor 1 To Support Its Replication |
| title_sort | hepatitis c virus induces the ubiquitin editing enzyme a20 via depletion of the transcription factor upstream stimulatory factor 1 to support its replication |
| topic | A20 ubiquitin enzyme HCV IRES USF-1 transcription factor hepatitis C virus |
| url | https://journals.asm.org/doi/10.1128/mBio.01660-19 |
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