Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit

Kerstin Schott, Nina V. Fuchs, Rita Derua, Bijan Mahboubi, Esther Schnellbächer, Janna Seifried, Christiane Tondera, Heike Schmitz, Caitlin Shepard, Alberto Brandariz-Nuñez, Felipe Diaz-Griffero, Andreas Reuter, Baek Kim, Veerle Janssens and Renate König ()
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Kerstin Schott: Paul-Ehrlich-Institut
Nina V. Fuchs: Paul-Ehrlich-Institut
Rita Derua: Laboratory of Protein Phosphorylation and Proteomics, KU Leuven
Bijan Mahboubi: Emory University, Children’s Healthcare of Atlanta
Esther Schnellbächer: Paul-Ehrlich-Institut
Janna Seifried: Paul-Ehrlich-Institut
Christiane Tondera: Paul-Ehrlich-Institut
Heike Schmitz: Paul-Ehrlich-Institut
Caitlin Shepard: Emory University, Children’s Healthcare of Atlanta
Alberto Brandariz-Nuñez: Albert Einstein College of Medicine
Felipe Diaz-Griffero: Albert Einstein College of Medicine
Andreas Reuter: Paul-Ehrlich-Institut
Baek Kim: Emory University, Children’s Healthcare of Atlanta
Veerle Janssens: Laboratory of Protein Phosphorylation and Proteomics, KU Leuven
Renate König: Paul-Ehrlich-Institut

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity is regulated by T592 phosphorylation. Here, we show that SAMHD1 dephosphorylation at T592 is controlled during the cell cycle, occurring during M/G1 transition in proliferating cells. Using several complementary proteomics and biochemical approaches, we identify the phosphatase PP2A-B55α responsible for rendering SAMHD1 antivirally active. SAMHD1 is specifically targeted by PP2A-B55α holoenzymes during mitotic exit, in line with observations that PP2A-B55α is a key mitotic exit phosphatase in mammalian cells. Strikingly, as HeLa or activated primary CD4+ T cells enter the G1 phase, pronounced reduction of RT products is observed upon HIV-1 infection dependent on the presence of dephosphorylated SAMHD1. Moreover, PP2A controls SAMHD1 pT592 level in non-cycling monocyte-derived macrophages (MDMs). Thus, the PP2A-B55α holoenzyme is a key regulator to switch on the antiviral activity of SAMHD1.

Date: 2018
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DOI: 10.1038/s41467-018-04671-1

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