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

Child, Matthew A.; Hall, Carolyn I; Beck, Josh R.; Ofori, Leslie O.; Albrow, Victoria E.; Garland, Megan; Bowyer, Paul W.; Bradley, Peter J.; Powers, James C.; Boothroyd, John C.; Weerapana, Eranthie; Bogyo, Matthew

doi:10.1038/nchembio.1315

Cited by 57 publications

(104 citation statements)

References 43 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…As such, palmitoylation of rhoptry proteins is critical for their correct cellular positioning. It has been described that inhibition of palmitoylation prevents the invasion process [16] and that palmitoylation exacerbation enhances the secretion of invasion-associated organelles thus increasing the invasive capacity of tachyzoites [17]. Whether this effect is related to palmitoylation of rhoptry proteins remains to be studied in more detail.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Identification of new palmitoylated proteins in Toxoplasma gondii

Caballero

Alonso

Deng

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

Protein palmitoylation has been shown to be an important post-translational modification in eukaryotic cells. This modification alters the localization and/or the function of the targeted protein. In the recent years protein palmitoylation has risen in importance in apicomplexan parasites as well. In Toxoplasma gondii, some proteins have been reported to be modified by palmitate. With the development of new techniques that allow the isolation of palmitoylated proteins, this significant post-translational modification has begun to be studied in more detail in T. gondii. Here we describe the palmitoylome of the tachyzoite stage of T. gondii using a combination of the acyl-biotin exchange chemistry method and mass spectrometry analysis. We identified 401 proteins found in multiple cellular compartments, with a wide range of functions that vary from metabolic processes, gliding and host-cell invasion to even regulation of transcription and translation. Besides, we found that more rhoptry proteins than the ones already described for Toxoplasma are palmitoylated, suggesting an important role for this modification in the invasion mechanism of the host-cell. This study documents that protein palmitoylation is a common modification in T. gondii that could have an impact on different cellular processes. Table S1: List of all non-redundant identified candidate proteins from the three independent ABE assays. The first worksheet tab contains a multiconsensus analysis showing proteins identified in all three assays together with their respective mass spectrometry information and in silico predictions. Highlighted in blue are those already described to palmitoylated, in grey are those predicted to be palmitoylated but without experimental evidence and in green those that have homology to known S-acylated proteins from P. falciparum. Tabs 2, 3 and 4 contain particular information and NRP calculations for each assay, while the last tab is a summary of the calculated NRP HA+/HA-ratios calculated for each protein.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Furthermore, inhibition of depalmitoylation enhances those same two processes [17]. This suggests that more proteins than the ones found to date must be targeted by palmitoylation.…”

Section: Introductionmentioning

confidence: 99%

Identification of new palmitoylated proteins in Toxoplasma gondii

Caballero

Alonso

Deng

et al. 2016

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

show abstract

“…4-Chloro-isocoumarin probes were identified to be highly selective for cathepsin G, elastase, and, to a lesser extent, uPA [20,21]. Furthermore, 4-chloro-isocoumarins capable of enhancing Toxoplasma gondii invasion by inhibiting the SH, palmitoyl protein thioesterase-1 (PPT1) were identified [22]. Despite the observed reactivity with activated serine residues, these electrophiles have been shown to react with other nucleophiles such as the thiol group in Protein-reactive electrophiles for chemical proteomics Shannon and Weerapana 19…”

Section: Covalent Modification Of Serinementioning

confidence: 99%

Covalent protein modification: the current landscape of residue-specific electrophiles

Shannon

Weerapana

2015

Current Opinion in Chemical Biology

Self Cite

198

178

View full text Add to dashboard Cite

“…The term APT could not be assigned to this gene in T. gondii since this abbreviation has already been used to describe an unrelated gene (Child et al, 2013;Kemp et al, 2013). TgPPT1 is a target of a small molecule inhibitor, chloroisocoumarin, which exhibits enhanced microneme secretion, motility and invasion efficiency (Child et al, 2013).…”

Section: Enzymes Implicated In Protein Depalmitoylationmentioning

confidence: 99%

Emerging roles for protein S-palmitoylation in Toxoplasma biology

Frénal

Kemp

Soldati‐Favre

2014

International Journal for Parasitology

View full text Add to dashboard Cite

a b s t r a c tPost-translational modifications are refined, rapidly responsive and powerful ways to modulate protein function. Among post-translational modifications, acylation is now emerging as a widespread modification exploited by eukaryotes, bacteria and viruses to control biological processes. Protein palmitoylation involves the attachment of palmitic acid, also known as hexadecanoic acid, to cysteine residues of integral and peripheral membrane proteins and increases their affinity for membranes. Importantly, similar to phosphorylation, palmitoylation is reversible and is becoming recognised as instrumental for the regulation of protein function by modulating protein interactions, stability, folding, trafficking and signalling. Palmitoylation appears to play a central role in the biology of the Apicomplexa, regulating critical processes such as host cell invasion which is vital for parasite survival and dissemination. The recent identification of over 400 palmitoylated proteins in Plasmodium falciparum erythrocytic stages illustrates the broad spread and impact of this modification on parasite biology. The main enzymes responsible for protein palmitoylation are multi-membrane protein S-acyl transferases harbouring a catalytic Asp-HisHis-Cys (DHHC) motif. A global functional analysis of the repertoire of protein S-acyl transferases in Toxoplasma gondii and Plasmodium berghei has recently been performed. The essential nature of some of these enzymes illustrates the key roles played by this post-translational modification in the corresponding substrates implicated in fundamental processes such as parasite motility and organelle biogenesis. Toward a better understanding of the depalmitoylation event, a protein with palmitoyl protein thioesterase activity has been identified in T. gondii. TgPPT1/TgASH1 is the main target of specific acyl protein thioesterase inhibitors but is dispensable for parasite survival, suggesting the implication of other genes in depalmitoylation. Palmitoylation/depalmitoylation cycles are now emerging as potential novel regulatory networks and T. gondii represents a superb model organism in which to explore their significance.

show abstract

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

Cited by 57 publications

References 43 publications

Identification of new palmitoylated proteins in Toxoplasma gondii

Identification of new palmitoylated proteins in Toxoplasma gondii

Covalent protein modification: the current landscape of residue-specific electrophiles

Emerging roles for protein S-palmitoylation in Toxoplasma biology

Contact Info

Product

Resources

About