Getting stuck in: protein palmitoylation in Plasmodium

Jones, Matthew L.; Tay, Chwen L.; Rayner, Julian C.

doi:10.1016/j.pt.2012.08.009

Cited by 17 publications

(22 citation statements)

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“…The yeast PAT called Akr1 is a member of this group [16], [20]. All these findings were crucial in defining palmitoylation as an enzymatic process and led to subsequent identification of protein acyltransferases in many other organisms, such as mammals [21], [22], plants [23], and protozoan parasites like Toxoplasma gondii [24], [25], Plasmodium [26], [25], and Trypanosoma brucei [27].…”

Section: Introductionmentioning

confidence: 99%

Identification of Giardia lamblia DHHC Proteins and the Role of Protein S-palmitoylation in the Encystation Process

et al. 2014

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Protein S-palmitoylation, a hydrophobic post-translational modification, is performed by protein acyltransferases that have a common DHHC Cys-rich domain (DHHC proteins), and provides a regulatory switch for protein membrane association. In this work, we analyzed the presence of DHHC proteins in the protozoa parasite Giardia lamblia and the function of the reversible S-palmitoylation of proteins during parasite differentiation into cyst. Two specific events were observed: encysting cells displayed a larger amount of palmitoylated proteins, and parasites treated with palmitoylation inhibitors produced a reduced number of mature cysts. With bioinformatics tools, we found nine DHHC proteins, potential protein acyltransferases, in the Giardia proteome. These proteins displayed a conserved structure when compared to different organisms and are distributed in different monophyletic clades. Although all Giardia DHHC proteins were found to be present in trophozoites and encysting cells, these proteins showed a different intracellular localization in trophozoites and seemed to be differently involved in the encystation process when they were overexpressed. dhhc transgenic parasites showed a different pattern of cyst wall protein expression and yielded different amounts of mature cysts when they were induced to encyst. Our findings disclosed some important issues regarding the role of DHHC proteins and palmitoylation during Giardia encystation.

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Section: Introductionmentioning

confidence: 99%

Identification of Giardia lamblia DHHC Proteins and the Role of Protein S-palmitoylation in the Encystation Process

et al. 2014

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“…Posttranslational modifications, such as lipidation, can increase the affinity of a modified protein for membranes and alter its subcellular localization. Only palmitoylation-the addition of a C-16 long-chain fatty acid to a cysteine residue-is reversible and thus able to dynamically influence protein-protein interactions, function, and gene expression (12)(13)(14)(15)(16)(17).Catalyzed by TM-spanning enzymes known as palmitoyl-S-acyltransferases (DHHC-PATs; PATs) this posttranslational modification is evolutionarily conserved; 25 PATs are known in humans, 7 in Saccharomyces cerevisiae, 12 in the human malaria parasite P. falciparum, and 11 in the rodent malaria parasite Plasmodium berghei.In asexual blood stages of P. falciparum, several hundred proteins have been found to be palmitoylated, and the addition of the inhibitor 2-bromopalmitate (2-BMP) to P. falciparum in vitro cultures is known to cause developmental as well as red blood cell invasion defects in schizonts, the latter likely through the destabilization of gliding motility motor components (15). In P. berghei, the inhibitor causes severe ookinete formation defects (18).…”

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Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite

Santos

Duarte

Kehrer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Transmission of the malaria parasite from the mammalian host to the mosquito vector requires the formation of adequately adapted parasite forms and stage-specific organelles. Here we show that formation of the crystalloid-a unique and short-lived organelle of the Plasmodium ookinete and oocyst stage required for sporogonyis dependent on the precisely timed expression of the S-acyltransferase DHHC10. DHHC10, translationally repressed in female Plasmodium berghei gametocytes, is activated translationally during ookinete formation, where the protein is essential for the formation of the crystalloid, the correct targeting of crystalloid-resident protein LAP2, and malaria parasite transmission.T he malaria parasite is capable of infecting both the vertebrate host and mosquito vector. After a mosquito blood meal, sexual precursor cells rapidly differentiate into mature gametes. In the mosquito midgut, the gametes mate to form a zygote that develops further into the motile ookinete. After crossing the midgut epithelium and establishing a sessile oocyst, the ookinete gives rise to thousands of sporozoites capable of infecting a subsequent mammalian host (1).Sharing key organelles like the nucleus, endoplasmic reticulum, Golgi, and mitochondria with other eukaryotes, this parasite has evolved specialized, stage-specific structures that are necessary for developmental progression during parasite transmission. These include, for example, osmiophilic bodies (secretory vesicles) that release protein factors capable of lysing the parasitophorous vacuole and erythrocyte membranes, thus producing free gametes (2) and a gliding motility motor anchored to the inner membrane complex (IMC), allowing the ookinete to migrate across the mosquito midgut epithelium and establish an oocyst (3). Sporozoite formation in the oocyst finally requires the presence of a stage-specific organelle, the crystalloid, a multivesicular structure assembled in the ookinete and putative reservoir of proteins and lipids used during sporogony. Although this enigmatic organelle was discovered more than 40 y ago, its formation and function remain largely unknown (4-9). Six LCCL proteins have been shown to reside within (9) and maintain the stability (8, 9) of these organelles essential for sporogony (10).The morphological changes taking place during zygote-toookinete development and the generation of thousands of sporozoites inside a single oocyst require extensive protein translation and membrane biogenesis to support the formation of organelles and plasma membrane (PM) surrounding each new parasite. Onethird of the proteins identified in the oocyst and oocyst-derived (midgut) sporozoites of the human parasite Plasmodium falciparum are putatively membrane-bound (11). The targeting of such proteins to organelles, and perhaps formation of certain organelles per se, requires appropriate sorting signals, along with transmembrane (TM) domains to keep these factors in place. Posttranslational modifications, such as lipidation, can increase the affinity of a modif...

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“…First, 18 and 12 genes coding for putative DHHC motif-containing protein S-acyltransferases are present in T. gondii and P. falciparum genomes, respectively (8,9), providing for the addition of palmitate to proteins in diverse subcellular compartments. Furthermore, a large num-ber of substrates have been predicted based on bioinformatics searches and identified in a palmitome analysis of P. falciparum (9,10). Additionally, palmitoylation of several apicomplexan proteins has been experimentally proven to be critical for correct protein localization and function (11)(12)(13)(14)(15).…”

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Characterization of a Serine Hydrolase Targeted by Acyl-protein Thioesterase Inhibitors in Toxoplasma gondii

Kemp

Rusch²,

Adibekian

et al. 2013

Journal of Biological Chemistry

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Background: S-Palmitoylation is an important reversible modification that involves the action of an acyl-protein thioesterase (APT). Results:We identified an active serine hydrolase (TgASH1) specifically targeted by human APT1 inhibitors in Toxoplasma gondii. Conclusion: TgASH1 is dispensable and cannot be solely responsible for S-depalmitoylation in Apicomplexa. Significance: ␤-Lactone-based APT1 inhibitors hit multiple targets in T. gondii and severely compromise parasite survival.

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Getting stuck in: protein palmitoylation in Plasmodium

Cited by 17 publications

References 60 publications

Identification of Giardia lamblia DHHC Proteins and the Role of Protein S-palmitoylation in the Encystation Process

Identification of Giardia lamblia DHHC Proteins and the Role of Protein S-palmitoylation in the Encystation Process

Maternally supplied S-acyl-transferase is required for crystalloid organelle formation and transmission of the malaria parasite

Characterization of a Serine Hydrolase Targeted by Acyl-protein Thioesterase Inhibitors in Toxoplasma gondii

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