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.

Details

Title
Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit
Author
Schott, Kerstin 1 ; Fuchs, Nina V 1 ; Derua, Rita 2 ; Mahboubi, Bijan 3 ; Schnellbächer, Esther 1 ; Seifried, Janna 1 ; Tondera, Christiane 1 ; Schmitz, Heike 1 ; Shepard, Caitlin 3 ; Brandariz-Nuñez, Alberto 4   VIAFID ORCID Logo  ; Diaz-Griffero, Felipe 4 ; Reuter, Andreas 5 ; Baek, Kim 6 ; Janssens, Veerle 7   VIAFID ORCID Logo  ; König, Renate 8 

1  Host-Pathogen Interactions, Paul-Ehrlich-Institut, Langen, Germany 
2  Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Leuven, Belgium; Facility for Systems Biology based Mass Spectrometry (SYBIOMA), KU Leuven, Leuven, Belgium 
3  Center for Drug Discovery, Department of Pediatrics, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USA 
4  Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA 
5  Division of Allergology, Paul-Ehrlich-Institut, Langen, Germany 
6  Center for Drug Discovery, Department of Pediatrics, Emory University, Children’s Healthcare of Atlanta, Atlanta, GA, USA; Department of Pharmacy, Kyung-Hee University, Seoul, South Korea 
7  Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, Leuven, Belgium 
8  Host-Pathogen Interactions, Paul-Ehrlich-Institut, Langen, Germany; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; German Center for Infection Research (DZIF), Langen, Germany 
Pages
1-16
Publication year
2018
Publication date
Jun 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-04671-1
ProQuest document ID
2052589298
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.