Human platelet protein ubiquitylation and changes following GPVI activation

Amanda Unsworth, Izabela Bombik, Adan Pinto-Fernandez, Joanna F. McGouran, Rebecca Konietzny, Rene P Konietzny, Steve Watson, Benedikt Kessler, Catherine J. Pears

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
156 Downloads (Pure)

Abstract

Platelet activators stimulate post-translational modification of signalling proteins to change their activity or their molecular interactions leading to signal propagation. One covalent modification is attachment of the small protein ubiquitin to lysine residues in target proteins. Modification by ubiquitin can either target proteins for degradation by the proteasome or act as a scaffold for other proteins. Pharmacological inhibition of deubiquitylases or the proteasome inhibits platelet activation by collagen, demonstrating a role for ubiquitylation, but relatively few substrates for ubiquitin have been identified and the molecular basis of inhibition is not established. Here we report the ubiquitome of human platelets and changes in ubiquitylated proteins following stimulation by collagen related peptide (CRP-XL). Using platelets from six individuals over three independent experiments, we identified 1634 ubiquitylated peptides derived from 691 proteins, revealing extensive ubiquitylation in resting platelets. 925 of these peptides show an increase of more than 2-fold following stimulation with CRP-XL. Multiple sites of ubiquitylation were identified on a number of proteins including Syk, filamin and integrin heterodimer subunits. This work reveals extensive protein ubiquitylation during activation of human platelets and opens the possibility of novel therapeutic interventions targeting the ubiquitin machinery.
Original languageEnglish
Pages (from-to)104-116
JournalThrombosis and Haemostasis
Volume119
Issue number1
DOIs
Publication statusPublished - 31 Dec 2018

Keywords

  • Platelets
  • sites of ubiquitinylation
  • GPVI
  • deubiquitylation inhibition

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