HIV-1 Vif Triggers Cell Cycle Arrest by Degrading Cellular PPP2R5 Phospho-regulators

Daniel J. Salamango; Terumasa Ikeda; Seyed Arad Moghadasi; Jiayi Wang; Jennifer L. McCann; Artur A. Serebrenik; Diako Ebrahimi; Matthew C. Jarvis; William L. Brown; Reuben S. Harris

Cell Reports (Oct 2019)

HIV-1 Vif Triggers Cell Cycle Arrest by Degrading Cellular PPP2R5 Phospho-regulators

Daniel J. Salamango,
Terumasa Ikeda,
Seyed Arad Moghadasi,
Jiayi Wang,
Jennifer L. McCann,
Artur A. Serebrenik,
Diako Ebrahimi,
Matthew C. Jarvis,
William L. Brown,
Reuben S. Harris

Affiliations

Daniel J. Salamango: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA; Corresponding author
Terumasa Ikeda: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA
Seyed Arad Moghadasi: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA
Jiayi Wang: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA
Jennifer L. McCann: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA
Artur A. Serebrenik: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA
Diako Ebrahimi: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA
Matthew C. Jarvis: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA
William L. Brown: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA
Reuben S. Harris: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA; Corresponding author

Journal volume & issue: Vol. 29, no. 5
pp. 1057 – 1065.e4

Abstract

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Summary: HIV-1 Vif hijacks a cellular ubiquitin ligase complex to degrade antiviral APOBEC3 enzymes and PP2A phosphatase regulators (PPP2R5A–E). APOBEC3 counteraction is essential for viral pathogenesis. However, Vif also functions through an unknown mechanism to induce G2 cell cycle arrest. Here, deep mutagenesis is used to define the Vif surface required for PPP2R5 degradation and isolate a panel of separation-of-function mutants (PPP2R5 degradation-deficient and APOBEC3G degradation-proficient). Functional studies with Vif and PPP2R5 mutants were combined to demonstrate that PPP2R5 is, in fact, the target Vif degrades to induce G2 arrest. Pharmacologic and genetic approaches show that direct modulation of PP2A function or depletion of specific PPP2R5 proteins causes an indistinguishable arrest phenotype. Vif function in the cell cycle checkpoint is present in common HIV-1 subtypes worldwide and likely advantageous for viral pathogenesis. : Salamango et al. discovered that the HIV-1 accessory protein Vif degrades several PP2A phospho-regulators to induce G2 cell cycle arrest. This activity is prevalent among diverse HIV-1 subtypes and global viral populations, suggesting that virus-induced G2 arrest is advantageous for pathogenesis. Keywords: cell cycle checkpoint, HIV-1, host-pathogen interaction, phosphatase regulation, Vif

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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