Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion

Nat Chem Biol. 2013 Oct;9(10):651-6. doi: 10.1038/nchembio.1315. Epub 2013 Aug 11.

Abstract

Although there have been numerous advances in our understanding of how apicomplexan parasites such as Toxoplasma gondii enter host cells, many of the signaling pathways and enzymes involved in the organization of invasion mediators remain poorly defined. We recently performed a forward chemical-genetic screen in T. gondii and identified compounds that markedly enhanced infectivity. Although molecular dissection of invasion has benefited from the use of small-molecule inhibitors, the mechanisms underlying induction of invasion by small-molecule enhancers have never been described. Here we identify the Toxoplasma ortholog of human APT1, palmitoyl protein thioesterase-1 (TgPPT1), as the target of one class of small-molecule enhancers. Inhibition of this uncharacterized thioesterase triggered secretion of invasion-associated organelles, increased motility and enhanced the invasive capacity of tachyzoites. We demonstrate that TgPPT1 is a bona fide depalmitoylase, thereby establishing an important role for dynamic and reversible palmitoylation in host-cell invasion by T. gondii.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Coumarins / chemistry
  • Coumarins / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / parasitology*
  • Humans
  • Molecular Structure
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Thiolester Hydrolases / antagonists & inhibitors*
  • Thiolester Hydrolases / genetics
  • Thiolester Hydrolases / metabolism
  • Toxoplasma / drug effects*
  • Toxoplasma / enzymology*
  • Toxoplasma / metabolism
  • Toxoplasma / pathogenicity

Substances

  • Coumarins
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Thiolester Hydrolases
  • palmitoyl-protein thioesterase

Associated data

  • PubChem-Substance/163711205
  • PubChem-Substance/163711206
  • PubChem-Substance/163711207
  • PubChem-Substance/163711208
  • PubChem-Substance/163711209
  • PubChem-Substance/163711210
  • PubChem-Substance/163711211
  • PubChem-Substance/163711212
  • PubChem-Substance/163711213
  • PubChem-Substance/163711214
  • PubChem-Substance/163711215
  • PubChem-Substance/163711216
  • PubChem-Substance/163711217
  • PubChem-Substance/163711218