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Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2013 Oct; Vol. 9 (10), pp. 651-6. Date of Electronic Publication: 2013 Aug 11. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Cell Line
Coumarins chemistry
Coumarins pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors chemistry
Epithelial Cells drug effects
Epithelial Cells metabolism
Humans
Molecular Structure
Small Molecule Libraries chemistry
Structure-Activity Relationship
Thiolester Hydrolases genetics
Thiolester Hydrolases metabolism
Toxoplasma metabolism
Toxoplasma pathogenicity
Enzyme Inhibitors pharmacology
Epithelial Cells parasitology
Small Molecule Libraries pharmacology
Thiolester Hydrolases antagonists & inhibitors
Toxoplasma drug effects
Toxoplasma enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 9
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 23934245
- Full Text :
- https://doi.org/10.1038/nchembio.1315