Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest
- University of Cambridge, United Kingdom
Abstract
The seminal description of the cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. We recently reported that HIV-1 Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E; Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 viruses in vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Proteomic datasets have been deposited to PRIDE, under the accession PXD018271, and are summarised in Source data files for Figures 2, 6 and 7.
Article and author information
Author details
Edward JD Greenwood
Nicholas J Matheson
Funding
Medical Research Council (MR/P008801/1)
- Nicholas J Matheson
NHS Blood and Transplant (WPA15-02)
- Nicholas J Matheson
Wellcome (210688/Z/18/Z)
- Paul J Lehner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Frank Kirchhoff, Ulm University Medical Center, Germany
Ethics
Human subjects: Ethical permission for this study was granted by the University of Cambridge Human Biology Research Ethics Committee (HBREC.2017.20). Written informed consent was obtained from all volunteers prior to providing blood samples.
Version history
- Received: October 31, 2019
- Accepted: March 17, 2020
- Accepted Manuscript published: April 15, 2020 (version 1)
- Version of Record published: March 1, 2021 (version 2)
Copyright
© 2020, Marelli et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest
eLife 9:e53036.
https://doi.org/10.7554/eLife.53036
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