Temporal proteomic analysis of HIV infection reveals remodelling of the host phosphoproteome by lentiviral Vif variants
- University of Cambridge, United Kingdom
Abstract
Viruses manipulate host factors to enhance their replication and evade cellular restriction. We used multiplex tandem mass tag (TMT)-based whole cell proteomics to perform a comprehensive time course analysis of >6,500 viral and cellular proteins during HIV infection. To enable specific functional predictions, we categorized cellular proteins regulated by HIV according to their patterns of temporal expression. We focussed on proteins depleted with similar kinetics to APOBEC3C, and found the viral accessory protein Vif to be necessary and sufficient for CUL5-dependent proteasomal degradation of all members of the B56 family of regulatory subunits of the key cellular phosphatase PP2A (PPP2R5A-E). Quantitative phosphoproteomic analysis of HIV-infected cells confirmed Vif-dependent hyperphosphorylation of >200 cellular proteins, particularly substrates of the aurora kinases. The ability of Vif to target PPP2R5 subunits is found in primate and non-primate lentiviral lineages, and remodeling of the cellular phosphoproteome is therefore a second ancient and conserved Vif function.
Data availability
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Temporal proteomic analysis of HIV-infection reveals remodelling of the cellular phosphoproteome by phylogenetically diverse lentiviral Vif variantsPublicly available at the EMBL PRIDE Archive (accession no: PXD004187).
Article and author information
Author details
Nicholas J Matheson
Funding
Wellcome Trust PRF (101835/Z/13/Z)
- Paul J Lehner
Wellcome Trust PRF (093964/Z/10/Z)
- Nicholas J Matheson
Addenbrooke's Charitable Trust, Cambridge University Hospitals
- Nicholas J Matheson
Raymond and Beverly Sackler Foundation
- Nicholas J Matheson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication
Reviewing Editor
- Éric A. Cohen, IRCM-UdeM Chair of Excellence in HIV Research, Canada
Version history
- Received: May 30, 2016
- Accepted: September 28, 2016
- Accepted Manuscript published: September 30, 2016 (version 1)
- Accepted Manuscript updated: October 1, 2016 (version 2)
- Version of Record published: October 28, 2016 (version 3)
Copyright
© 2016, Greenwood 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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Temporal proteomic analysis of HIV infection reveals remodelling of the host phosphoproteome by lentiviral Vif variants
eLife 5:e18296.
https://doi.org/10.7554/eLife.18296
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Survival of Mycobacterium tuberculosis within the host macrophages requires the bacterial virulence regulator PhoP, but the underlying reason remains unknown. 3′,5′-Cyclic adenosine monophosphate (cAMP) is one of the most widely used second messengers, which impacts a wide range of cellular responses in microbial pathogens including M. tuberculosis. Herein, we hypothesized that intra-bacterial cAMP level could be controlled by PhoP since this major regulator plays a key role in bacterial responses against numerous stress conditions. A transcriptomic analysis reveals that PhoP functions as a repressor of cAMP-specific phosphodiesterase (PDE) Rv0805, which hydrolyzes cAMP. In keeping with these results, we find specific recruitment of the regulator within the promoter region of rv0805 PDE, and absence of phoP or ectopic expression of rv0805 independently accounts for elevated PDE synthesis, leading to the depletion of intra-bacterial cAMP level. Thus, genetic manipulation to inactivate PhoP-rv0805-cAMP pathway decreases cAMP level, stress tolerance, and intracellular survival of the bacillus.
