Hsp90 inhibition induces both protein-specific and global changes in the ubiquitinome

Journal of Proteomics
Manfredo QuadroniPatrice Waridel

Abstract

Inhibition of the essential chaperone Hsp90 with drugs causes a global perturbation of protein folding and the depletion of direct substrates of Hsp90, also called clients. Ubiquitination and proteasomal degradation play a key role in cellular stress responses, but the impact of Hsp90 inhibition on the ubiquitinome has not been characterized on a global scale. We used stable isotope labeling and antibody-based peptide enrichment to quantify more than 1500 protein sites modified with a Gly-Gly motif, the remnant of ubiquitination, in human T-cells treated with an Hsp90 inhibitor. We observed rapid changes in GlyGly-modification sites, with strong increases for some Hsp90 clients but also decreases for a majority of cellular proteins. A comparison with changes in total protein levels and protein synthesis and decay rates from a previous study revealed a complex picture with different regulatory patterns observed for different protein families. Overall the data support the notion that for Hsp90 clients GlyGly-modification correlates with targeting by the ubiquitin-proteasome system and decay, while for other proteins levels of GlyGly-modification appear to be mainly influenced by their synthesis rates. Therefore a correct interpre...Continue Reading

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Citations

Oct 27, 2015·Biomolecules·Rosa PennisiAlessandra di Masi
Oct 11, 2017·Expert Review of Proteomics·Lorenz WeidenauerManfredo R Quadroni
Sep 28, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Dhaval SanchalaYogesh A Kulkarni
Mar 7, 2017·Analytical Chemistry·Albert CasanovasJoaquin Abian

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