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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...

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Autores principales: Takeuchi, Hiroaki, Saito, Hideki, Noda, Takeshi, Miyamoto, Tadashi, Yoshinaga, Tomokazu, Terahara, Kazutaka, Ishii, Hiroshi, Tsunetsugu-Yokota, Yasuko, Yamaoka, Shoji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
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.
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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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