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

• Main Authors: Hiroaki Takeuchi, Hideki Saito, Takeshi Noda, Tadashi Miyamoto, Tomokazu Yoshinaga, Kazutaka Terahara, Hiroshi Ishii, Yasuko Tsunetsugu-Yokota, Shoji Yamaoka
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2017-07-01
• Series: PLoS Pathogens
• Online Access: http://europepmc.org/articles/PMC5500366?pdf=render

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.