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Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis
Regulation of capsid disassembly is crucial for efficient HIV-1 cDNA synthesis after entry, yet host factors involved in this process remain largely unknown. Here, we employ genetic screening of human T-cells to identify maternal embryonic leucine zipper kinase (MELK) as a host factor required for o...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500366/ https://www.ncbi.nlm.nih.gov/pubmed/28683086 http://dx.doi.org/10.1371/journal.ppat.1006441 |
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author | Takeuchi, Hiroaki Saito, Hideki Noda, Takeshi Miyamoto, Tadashi Yoshinaga, Tomokazu Terahara, Kazutaka Ishii, Hiroshi Tsunetsugu-Yokota, Yasuko Yamaoka, Shoji |
author_facet | Takeuchi, Hiroaki Saito, Hideki Noda, Takeshi Miyamoto, Tadashi Yoshinaga, Tomokazu Terahara, Kazutaka Ishii, Hiroshi Tsunetsugu-Yokota, Yasuko Yamaoka, Shoji |
author_sort | Takeuchi, Hiroaki |
collection | PubMed |
description | Regulation of capsid disassembly is crucial for efficient HIV-1 cDNA synthesis after entry, yet host factors involved in this process remain largely unknown. Here, we employ genetic screening of human T-cells to identify maternal embryonic leucine zipper kinase (MELK) as a host factor required for optimal uncoating of the HIV-1 core to promote viral cDNA synthesis. Depletion of MELK inhibited HIV-1 cDNA synthesis with a concomitant delay of capsid disassembly. MELK phosphorylated Ser-149 of the capsid in the multimerized HIV-1 core, and a mutant virus carrying a phosphorylation-mimetic amino-acid substitution of Ser-149 underwent premature capsid disassembly and earlier HIV-1 cDNA synthesis, and eventually failed to enter the nucleus. Moreover, a small-molecule MELK inhibitor reduced the efficiency of HIV-1 replication in peripheral blood mononuclear cells in a dose-dependent manner. These results reveal a previously unrecognized mechanism of HIV-1 capsid disassembly and implicate MELK as a potential target for anti-HIV therapy. |
format | Online Article Text |
id | pubmed-5500366 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-55003662017-07-11 Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis Takeuchi, Hiroaki Saito, Hideki Noda, Takeshi Miyamoto, Tadashi Yoshinaga, Tomokazu Terahara, Kazutaka Ishii, Hiroshi Tsunetsugu-Yokota, Yasuko Yamaoka, Shoji PLoS Pathog Research Article Regulation of capsid disassembly is crucial for efficient HIV-1 cDNA synthesis after entry, yet host factors involved in this process remain largely unknown. Here, we employ genetic screening of human T-cells to identify maternal embryonic leucine zipper kinase (MELK) as a host factor required for optimal uncoating of the HIV-1 core to promote viral cDNA synthesis. Depletion of MELK inhibited HIV-1 cDNA synthesis with a concomitant delay of capsid disassembly. MELK phosphorylated Ser-149 of the capsid in the multimerized HIV-1 core, and a mutant virus carrying a phosphorylation-mimetic amino-acid substitution of Ser-149 underwent premature capsid disassembly and earlier HIV-1 cDNA synthesis, and eventually failed to enter the nucleus. Moreover, a small-molecule MELK inhibitor reduced the efficiency of HIV-1 replication in peripheral blood mononuclear cells in a dose-dependent manner. These results reveal a previously unrecognized mechanism of HIV-1 capsid disassembly and implicate MELK as a potential target for anti-HIV therapy. Public Library of Science 2017-07-06 /pmc/articles/PMC5500366/ /pubmed/28683086 http://dx.doi.org/10.1371/journal.ppat.1006441 Text en © 2017 Takeuchi et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Takeuchi, Hiroaki Saito, Hideki Noda, Takeshi Miyamoto, Tadashi Yoshinaga, Tomokazu Terahara, Kazutaka Ishii, Hiroshi Tsunetsugu-Yokota, Yasuko Yamaoka, Shoji Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis |
title | Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis |
title_full | Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis |
title_fullStr | Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis |
title_full_unstemmed | Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis |
title_short | Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis |
title_sort | phosphorylation of the hiv-1 capsid by melk triggers uncoating to promote viral cdna synthesis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500366/ https://www.ncbi.nlm.nih.gov/pubmed/28683086 http://dx.doi.org/10.1371/journal.ppat.1006441 |
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