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Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis.


ABSTRACT: 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.

SUBMITTER: Takeuchi H 

PROVIDER: S-EPMC5500366 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis.

Takeuchi Hiroaki H   Saito Hideki H   Noda Takeshi T   Miyamoto Tadashi T   Yoshinaga Tomokazu T   Terahara Kazutaka K   Ishii Hiroshi H   Tsunetsugu-Yokota Yasuko Y   Yamaoka Shoji S  

PLoS pathogens 20170706 7


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  ...[more]

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