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; Renate König

doi:10.1038/s41467-018-04671-1

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, Renate König

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	2227
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04671-1
State	Published - Dec 1 2018

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Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-018-04671-1

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Schott, K., Fuchs, N. V., Derua, R., Mahboubi, B., Schnellbächer, E., Seifried, J., Tondera, C., Schmitz, H., Shepard, C., Brandariz-Nuñez, A., Diaz-Griffero, F., Reuter, A., Kim, B., Janssens, V., & König, R. (2018). Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit. Nature communications, 9(1), Article 2227. https://doi.org/10.1038/s41467-018-04671-1

Schott, K, Fuchs, NV, Derua, R, Mahboubi, B, Schnellbächer, E, Seifried, J, Tondera, C, Schmitz, H, Shepard, C, Brandariz-Nuñez, A, Diaz-Griffero, F, Reuter, A, Kim, B, Janssens, V & König, R 2018, 'Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit', Nature communications, vol. 9, no. 1, 2227. https://doi.org/10.1038/s41467-018-04671-1

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

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.",

author = "Kerstin Schott and Fuchs, {Nina V.} and Rita Derua and Bijan Mahboubi and Esther Schnellb{\"a}cher and Janna Seifried and Christiane Tondera and Heike Schmitz and Caitlin Shepard and Alberto Brandariz-Nu{\~n}ez and Felipe Diaz-Griffero and Andreas Reuter and Baek Kim and Veerle Janssens and Renate K{\"o}nig",

note = "Funding Information: This work is supported by Deutsche Forschungsgemeinschaft (DFG): CRC1292 project TP04 and SPP1923 project KO 4573/1-1 to R.K., BMBF 01KI1307A and German Center for Infection Research (DZIF) HZI2010Z10, DZIF TTU 01.802 to R.K. V.J. and R. D. were supported by the IAP Program of the Belgian federal government (P7/13) and the KU Leuven Research Council (OT/13/094). A.B.N. and F.D.G. were supported by an NIH R01 GM123540 grant to F.D.G. B.K., B.M. and C.S. were supported by R01 GM104198 and R01 AI136581 to B.K. Funding Information: The authors thank Anna-Maria Engin, Nicole Gorgs, and Michaela Neuenkirch for technical assistance as well as Maximilian Rie{\ss}, Manja Burggraf, and Andreas Sommer for experimental support/critical discussion. Additionally, The authors thank Oliver T. Keppler (LMU Munich, Germany; for anti-SAMHD1 pT592 antibody), Sumit K. Chanda (Sanford Burnham Prebys Medical Discovery Institute, USA; for siRNAs), Nevan J. Krogan (University of California San Francisco (UCSF), USA; for plasmids encoding HIV-1 accessory proteins), Nathaniel R. Landau (NYU School of Medicine, USA; for pNL4.3 plasmids), Georg Kochs (University of Freiburg, Germany; for Sendai virus), Daniel Gerlich (University of Vienna, Austria; for HeLa {\textquoteleft}Kyoto{\textquoteright} cells), and Stephen Dilworth (Middlesex University London, UK; for monoclonal PP2A C antibodies) for reagents. This work is supported by Deutsche Forschungsgemeinschaft (DFG): CRC1292 project TP04 and SPP1923 project KO 4573/1-1 to R.K., BMBF 01KI1307A and German Center for Infection Research (DZIF) HZI2010Z10, DZIF TTU 01.802 to R.K. V.J. and R. D. were supported by the IAP Program of the Belgian federal government (P7/13) and the KU Leuven Research Council (OT/13/094). A.B.N. and F.D.G. were supported by an NIH R01 GM123540 grant to F.D.G. B.K., B.M. and C.S. were supported by R01 GM104198 and R01 AI136581 to B.K. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-04671-1",

language = "English (US)",

volume = "9",

journal = "Nature communications",

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T1 - Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit

AU - Schott, Kerstin

AU - Fuchs, Nina V.

AU - Derua, Rita

AU - Mahboubi, Bijan

AU - Schnellbächer, Esther

AU - Seifried, Janna

AU - Tondera, Christiane

AU - Schmitz, Heike

AU - Shepard, Caitlin

AU - Brandariz-Nuñez, Alberto

AU - Diaz-Griffero, Felipe

AU - Reuter, Andreas

AU - Kim, Baek

AU - Janssens, Veerle

AU - König, Renate

N1 - Funding Information: This work is supported by Deutsche Forschungsgemeinschaft (DFG): CRC1292 project TP04 and SPP1923 project KO 4573/1-1 to R.K., BMBF 01KI1307A and German Center for Infection Research (DZIF) HZI2010Z10, DZIF TTU 01.802 to R.K. V.J. and R. D. were supported by the IAP Program of the Belgian federal government (P7/13) and the KU Leuven Research Council (OT/13/094). A.B.N. and F.D.G. were supported by an NIH R01 GM123540 grant to F.D.G. B.K., B.M. and C.S. were supported by R01 GM104198 and R01 AI136581 to B.K. Funding Information: The authors thank Anna-Maria Engin, Nicole Gorgs, and Michaela Neuenkirch for technical assistance as well as Maximilian Rieß, Manja Burggraf, and Andreas Sommer for experimental support/critical discussion. Additionally, The authors thank Oliver T. Keppler (LMU Munich, Germany; for anti-SAMHD1 pT592 antibody), Sumit K. Chanda (Sanford Burnham Prebys Medical Discovery Institute, USA; for siRNAs), Nevan J. Krogan (University of California San Francisco (UCSF), USA; for plasmids encoding HIV-1 accessory proteins), Nathaniel R. Landau (NYU School of Medicine, USA; for pNL4.3 plasmids), Georg Kochs (University of Freiburg, Germany; for Sendai virus), Daniel Gerlich (University of Vienna, Austria; for HeLa ‘Kyoto’ cells), and Stephen Dilworth (Middlesex University London, UK; for monoclonal PP2A C antibodies) for reagents. This work is supported by Deutsche Forschungsgemeinschaft (DFG): CRC1292 project TP04 and SPP1923 project KO 4573/1-1 to R.K., BMBF 01KI1307A and German Center for Infection Research (DZIF) HZI2010Z10, DZIF TTU 01.802 to R.K. V.J. and R. D. were supported by the IAP Program of the Belgian federal government (P7/13) and the KU Leuven Research Council (OT/13/094). A.B.N. and F.D.G. were supported by an NIH R01 GM123540 grant to F.D.G. B.K., B.M. and C.S. were supported by R01 GM104198 and R01 AI136581 to B.K. Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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

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