Garcinol inhibits GCN5-mediated lysine acetyltransferase activity and prevents replication of the parasite Toxoplasma gondii

Victoria Jeffers, Hongyu Gao, Lisa A. Checkley, Yunlong Liu, Michael T. Ferdig, William Sullivan

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Lysine acetylation is a critical posttranslational modification that influences protein activity, stability, and binding properties. The acetylation of histone proteins in particular is a well-characterized feature of gene expression regulation. In the protozoan parasite Toxoplasma gondii, a number of lysine acetyltransferases (KATs) contribute to gene expression and are essential for parasite viability. The natural product garcinol was recently reported to inhibit enzymatic activities of GCN5 and p300 family KATs in other species. Here we show that garcinol inhibits TgGCN5b, the only nuclear GCN5 family KAT known to be required for Toxoplasma tachyzoite replication. Treatment of tachyzoites with garcinol led to a reduction of global lysine acetylation, particularly on histone H3 and TgGCN5b itself. We also performed transcriptome sequencing (RNA-seq), which revealed increasing aberrant gene expression coincident with increasing concentrations of garcinol. The majority of the genes that were most significantly affected by garcinol were also associated with TgGCN5b in a previously reported chromatin immunoprecipitation assay with microarray technology (ChIP-chip) analysis. The dysregulated gene expression induced by garcinol significantly inhibits Toxoplasma tachyzoite replication, and the concentrations used exhibit no overt toxicity on human host cells. Garcinol also inhibits Plasmodium falciparum asexual replication with a 50% inhibitory concentration (IC50) similar to that for Toxoplasma. Together, these data support that pharmacological inhibition of TgGCN5b leads to a catastrophic failure in gene expression control that prevents parasite replication.

Original languageEnglish (US)
Pages (from-to)2164-2170
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number4
DOIs
StatePublished - Apr 1 2016

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Toxoplasma
Parasites
Acetylation
Gene Expression
Histones
Inhibitory Concentration 50
Lysine
Communicable Disease Control
RNA Sequence Analysis
Protein Stability
Chromatin Immunoprecipitation
Gene Expression Regulation
Plasmodium falciparum
Post Translational Protein Processing
garcinol
Lysine Acetyltransferases
Biological Products
Nuclear Family
Transcriptome
Protein Binding

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Garcinol inhibits GCN5-mediated lysine acetyltransferase activity and prevents replication of the parasite Toxoplasma gondii. / Jeffers, Victoria; Gao, Hongyu; Checkley, Lisa A.; Liu, Yunlong; Ferdig, Michael T.; Sullivan, William.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 4, 01.04.2016, p. 2164-2170.

Research output: Contribution to journalArticle

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