MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in macrophages
ABSTRACT The type 1 interferon-regulated E3 ubiquitin ligase MARCH1 reduces surface expression of HIV-1 envelope glycoproteins (Env) and their packaging into nascent virions, a condition that restricts viral infectivity. However, how HIV-1 counters this restriction, notably during infection of macro...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-10-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01950-23 |
| _version_ | 1827150328117592064 |
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| author | Robert Lodge Zaikun Xu Mckenna Eklund Christina Stürzel Frank Kirchhoff Michel J. Tremblay Tom C. Hobman Éric A. Cohen |
| author_facet | Robert Lodge Zaikun Xu Mckenna Eklund Christina Stürzel Frank Kirchhoff Michel J. Tremblay Tom C. Hobman Éric A. Cohen |
| author_sort | Robert Lodge |
| collection | DOAJ |
| description | ABSTRACT The type 1 interferon-regulated E3 ubiquitin ligase MARCH1 reduces surface expression of HIV-1 envelope glycoproteins (Env) and their packaging into nascent virions, a condition that restricts viral infectivity. However, how HIV-1 counters this restriction, notably during infection of macrophages, remains unclear. Here, we show that the HIV-1 accessory protein Vpu increases the levels of microRNAs-25 and -93 to target MARCH1 mRNA. By recruiting β-TRCP, a component of the SCFβ-TRCP E3 ligase complex that targets phosphorylated β-catenin for degradation, Vpu increases β-catenin levels, which, in concert with TCF4/LEF, drives transcription of the MARCH1-targeting microRNAs. This potentiates HIV-1 infectivity as a result of increased Env incorporation into nascent virions. Pharmacological targeting of the β-catenin pathway inhibits Vpu-mediated upregulation of microRNAs-25 and -93 and restores MARCH1 restriction on HIV-1 infectivity. Overall, our findings highlight a novel mechanism by which HIV-1 counteracts MARCH1 by downregulating its expression via Vpu-mediated induction of microRNAs-25 and -93. IMPORTANCE In order to efficiently produce infectious viral particles, HIV must counter several restrictions exerted by host cell antiviral proteins. MARCH1 is a member of the MARCH protein family that restricts HIV infection by limiting the incorporation of viral envelope glycoproteins into nascent virions. Here, we identified two regulatory RNAs, microRNAs-25 and -93, induced by the HIV-1 accessory protein Vpu, that downregulate MARCH1 mRNA. We also show that Vpu induces these cellular microRNAs in macrophages by hijacking the cellular β-catenin pathway. The notion that HIV-1 has evolved a mechanism to counteract MARCH1 restriction on viral infectivity underlines the importance of MARCH1 in the host antiviral response. |
| first_indexed | 2024-03-11T08:30:51Z |
| format | Article |
| id | doaj.art-d691c612579c4ccfb0b25dd7e74b1bb7 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2025-03-20T21:32:20Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-d691c612579c4ccfb0b25dd7e74b1bb72024-08-11T18:20:46ZengAmerican Society for MicrobiologymBio2150-75112023-10-0114510.1128/mbio.01950-23MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in macrophagesRobert Lodge0Zaikun Xu1Mckenna Eklund2Christina Stürzel3Frank Kirchhoff4Michel J. Tremblay5Tom C. Hobman6Éric A. Cohen7Laboratory of Human Retrovirology, Institut de recherches cliniques de Montréal (IRCM) , Montreal, Quebec, CanadaDepartment of Cell Biology, University of Alberta , Edmonton, Alberta, CanadaDepartment of Cell Biology, University of Alberta , Edmonton, Alberta, CanadaInstitute of Molecular Virology, Ulm University Medical Center , Ulm, GermanyInstitute of Molecular Virology, Ulm University Medical Center , Ulm, GermanyCentre de recherche du centre hospitalier universitaire de Québec, Université Laval , Quebec City, Quebec, CanadaDepartment of Cell Biology, University of Alberta , Edmonton, Alberta, CanadaLaboratory of Human Retrovirology, Institut de recherches cliniques de Montréal (IRCM) , Montreal, Quebec, CanadaABSTRACT The type 1 interferon-regulated E3 ubiquitin ligase MARCH1 reduces surface expression of HIV-1 envelope glycoproteins (Env) and their packaging into nascent virions, a condition that restricts viral infectivity. However, how HIV-1 counters this restriction, notably during infection of macrophages, remains unclear. Here, we show that the HIV-1 accessory protein Vpu increases the levels of microRNAs-25 and -93 to target MARCH1 mRNA. By recruiting β-TRCP, a component of the SCFβ-TRCP E3 ligase complex that targets phosphorylated β-catenin for degradation, Vpu increases β-catenin levels, which, in concert with TCF4/LEF, drives transcription of the MARCH1-targeting microRNAs. This potentiates HIV-1 infectivity as a result of increased Env incorporation into nascent virions. Pharmacological targeting of the β-catenin pathway inhibits Vpu-mediated upregulation of microRNAs-25 and -93 and restores MARCH1 restriction on HIV-1 infectivity. Overall, our findings highlight a novel mechanism by which HIV-1 counteracts MARCH1 by downregulating its expression via Vpu-mediated induction of microRNAs-25 and -93. IMPORTANCE In order to efficiently produce infectious viral particles, HIV must counter several restrictions exerted by host cell antiviral proteins. MARCH1 is a member of the MARCH protein family that restricts HIV infection by limiting the incorporation of viral envelope glycoproteins into nascent virions. Here, we identified two regulatory RNAs, microRNAs-25 and -93, induced by the HIV-1 accessory protein Vpu, that downregulate MARCH1 mRNA. We also show that Vpu induces these cellular microRNAs in macrophages by hijacking the cellular β-catenin pathway. The notion that HIV-1 has evolved a mechanism to counteract MARCH1 restriction on viral infectivity underlines the importance of MARCH1 in the host antiviral response.https://journals.asm.org/doi/10.1128/mbio.01950-23human immunodeficiency virusmicroRNArestriction factorviral glycoproteinsMARCH proteinsHIV-1 countermeasures |
| spellingShingle | Robert Lodge Zaikun Xu Mckenna Eklund Christina Stürzel Frank Kirchhoff Michel J. Tremblay Tom C. Hobman Éric A. Cohen MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in macrophages mBio human immunodeficiency virus microRNA restriction factor viral glycoproteins MARCH proteins HIV-1 countermeasures |
| title | MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in macrophages |
| title_full | MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in macrophages |
| title_fullStr | MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in macrophages |
| title_full_unstemmed | MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in macrophages |
| title_short | MicroRNA-25/93 induction by Vpu as a mechanism for counteracting MARCH1-restriction on HIV-1 infectivity in macrophages |
| title_sort | microrna 25 93 induction by vpu as a mechanism for counteracting march1 restriction on hiv 1 infectivity in macrophages |
| topic | human immunodeficiency virus microRNA restriction factor viral glycoproteins MARCH proteins HIV-1 countermeasures |
| url | https://journals.asm.org/doi/10.1128/mbio.01950-23 |
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