Lysine acetyltransfer supports platelet function

J. E. Aslan, R. A. Rigg, M. S. Nowak, C. P. Loren, S. M. Baker-Groberg, J. Pang, L. L. David, O. J.T. Mccarty

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background and Objectives: The reversible acetylation of protein lysine ε-amino groups, catalyzed by lysine acetyltransferases and deacetylases, serves as a molecular switch in the orchestration of diverse cellular activities. Here, we aimed to investigate the role of lysine acetyltransfer in platelet function. Methods and Results: Proteomics methods identified 552 acetyllysine (acK) modifications on 273 platelet proteins that serve as candidate substrates for lysine acetyltransferases. Bioinformatics analyses of the identified acK-modified platelet proteins supported roles for the lysine acetyltransferase p300 in the regulation of actin-mediated platelet processes. Biochemical experiments showed that platelets express p300, which is activated in an Src kinase-dependent manner upon platelet stimulation with the platelet glycoprotein VI agonist collagen-related peptide (CRP). Inhibition of platelet p300 abrogated CRP-stimulated lysine acetylation of actin, filamin, and cortactin, as well as F-actin polymerization, integrin activation, and platelet aggregation. Super-resolution visualization of platelet actin-rich adhesion structures revealed abundant acK protein colocalized with platelet actin cytoskeletal proteins. Inhibition of p300 blocked platelet filopodium formation and the spreading of platelets on fibrinogen and collagen surfaces. In whole blood, p300 inhibition prevented the formation of platelet aggregates under shear, suggesting a physiologic role for lysine acetyltransferase activity in platelet function. Conclusion: Together, our findings reveal lysine acetyltransfer to be a potential regulator of platelet actin dynamics, and potential roles for lysine acetylation in the molecular coordination of platelet activation and function.

Original languageEnglish (US)
Pages (from-to)1908-1917
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2015

Keywords

  • Acetyltransferases
  • Actin
  • Metabolism
  • P300 acetyltransferase
  • Platelets

ASJC Scopus subject areas

  • Hematology

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