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A Facile Protocol to Generate Site-Specifically Acetylated Proteins in Escherichia Coli
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Acetylation site specificities of lysine deacetylase inhibitors in human cells

Christian Schölz1, Brian T Weinert1, Sebastian A Wagner1

  • 1Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Nature Biotechnology
|March 10, 2015
PubMed

Insights

This study characterizes the specificities of 19 lysine deacetylase inhibitors (KDACIs) using mass spectrometry. Results reveal distinct acetylation signatures for each KDACI, offering insights into their cellular functions and potential therapeutic applications.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Lysine deacetylase inhibitors (KDACIs) are crucial tools in research and clinical trials for cancer and other diseases.
  • The cellular specificities of most KDACIs remain incompletely understood, limiting their precise application.

Purpose of the Study:

  • To comprehensively characterize the specificities of 19 different KDACIs across all 18 human lysine deacetylases.
  • To elucidate the acetylation signatures induced by KDACIs and their impact on cellular proteins.

Main Methods:

  • Quantitative mass spectrometry (MS) was employed to analyze acetylation changes induced by 19 KDACIs.
  • Integrated analysis of inhibitor treatment and genetic deletion was used to confirm target engagement and effects.

Main Results:

  • Most KDACIs induced specific changes in acetylation, primarily affecting histones and chromatin-associated proteins.
  • The study confirmed nicotinamide's effects are mainly via SIRT1 inhibition and tubacin/bufexamac's via HDAC6 inhibition.
  • Bufexamac was found to induce a hypoxia-like response independent of HDAC6 inhibition by stabilizing HIF1-α.

Conclusions:

  • The findings provide a systems-level understanding of KDACI specificities and their impact on the cellular acetylome.
  • This work establishes a framework for investigating the roles of acetylation and deacetylases in biological processes and disease.
  • The results offer mechanistic insights into KDACI actions, including potential adverse effects like inflammation.

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