{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T09:38:28Z","timestamp":1777541908825,"version":"3.51.4"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,11,3]],"date-time":"2015-11-03T00:00:00Z","timestamp":1446508800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,11,3]],"date-time":"2015-11-03T00:00:00Z","timestamp":1446508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The post-translational addition of C-16 long chain fatty acids to protein cysteine residues is catalysed by palmitoyl-S-acyl-transferases (PAT) and affects the affinity of a modified protein for membranes and therefore its subcellular localisation. In apicomplexan parasites this reversible protein modification regulates numerous biological processes and specifically affects cell motility and invasion of host cells by <jats:italic>Plasmodium falciparum<\/jats:italic> merozoites and <jats:italic>Toxoplasma gondii<\/jats:italic> tachyzoites. Using inhibitor studies we show here that palmitoylation is key to transformation of zygotes into ookinetes during initial mosquito infection with <jats:italic>P. berghei<\/jats:italic>. We identify DHHC2 as a unique PAT mediating ookinete formation and morphogenesis. Essential for life cycle progression in asexual blood stage parasites and thus refractory to gene deletion analyses, we used promoter swap (ps) methodology to maintain <jats:italic>dhhc2<\/jats:italic> expression in asexual blood stages but down regulate expression in sexual stage parasites and during post-fertilization development of the zygote. The <jats:italic>ps<\/jats:italic> mutant showed normal gamete formation, fertilisation and DNA replication to tetraploid cells, but was characterised by a complete block in post-fertilisation development and ookinete formation. Our report highlights the crucial nature of the DHHC2 palmitoyl-S-acyltransferase for transmission of the malaria parasite to the mosquito vector through its essential role for ookinete morphogenesis.<\/jats:p>","DOI":"10.1038\/srep16034","type":"journal-article","created":{"date-parts":[[2015,11,3]],"date-time":"2015-11-03T09:56:53Z","timestamp":1446544613000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["The Plasmodium palmitoyl-S-acyl-transferase DHHC2 is essential for ookinete morphogenesis and malaria transmission"],"prefix":"10.1038","volume":"5","author":[{"given":"Jorge M.","family":"Santos","sequence":"first","affiliation":[]},{"given":"Jessica","family":"Kehrer","sequence":"additional","affiliation":[]},{"given":"Blandine","family":"Franke-Fayard","sequence":"additional","affiliation":[]},{"given":"Friedrich","family":"Frischknecht","sequence":"additional","affiliation":[]},{"given":"Chris J.","family":"Janse","sequence":"additional","affiliation":[]},{"given":"Gunnar R.","family":"Mair","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2015,11,3]]},"reference":[{"key":"BFsrep16034_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1186\/s13059-014-0493-0","volume":"15","author":"A Guerreiro","year":"2014","unstructured":"Guerreiro, A. et al. Genome-wide RIP-Chip analysis of translational repressor-bound mRNAs in the Plasmodium gametocyte. Genome Biol 15, 493 (2014).","journal-title":"Genome Biol"},{"key":"BFsrep16034_CR2","doi-asserted-by":"publisher","first-page":"e1000767","DOI":"10.1371\/journal.ppat.1000767","volume":"6","author":"GR Mair","year":"2010","unstructured":"Mair, G. R. et al. Universal features of post-transcriptional gene regulation are critical for Plasmodium zygote development. PLoS Pathog 6, e1000767 (2010).","journal-title":"PLoS Pathog"},{"key":"BFsrep16034_CR3","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1126\/science.1125129","volume":"313","author":"GR Mair","year":"2006","unstructured":"Mair, G. R. et al. Regulation of sexual development of Plasmodium by translational repression. Science 313, 667\u20139 (2006).","journal-title":"Science"},{"key":"BFsrep16034_CR4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.chom.2012.05.014","volume":"12","author":"S Sebastian","year":"2012","unstructured":"Sebastian, S. et al. A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs. Cell Host Microbe 12, 9\u201319 (2012).","journal-title":"Cell Host Microbe"},{"key":"BFsrep16034_CR5","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1242\/bio.20136163","volume":"2","author":"B Poulin","year":"2013","unstructured":"Poulin, B. et al. Unique apicomplexan IMC sub-compartment proteins are early markers for apical polarity in the malaria parasite. Biol Open 2, 1160\u201370 (2013).","journal-title":"Biol Open"},{"key":"BFsrep16034_CR6","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.pt.2008.08.006","volume":"24","author":"J Baum","year":"2008","unstructured":"Baum, J., Gilberger, T. W., Frischknecht, F. & Meissner, M. Host-cell invasion by malaria parasites: insights from Plasmodium and Toxoplasma. Trends Parasitol 24, 557\u201363 (2008).","journal-title":"Trends Parasitol"},{"key":"BFsrep16034_CR7","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.jsb.2015.02.008","volume":"190","author":"LE Boucher","year":"2015","unstructured":"Boucher, L. E. & Bosch, J. The apicomplexan glideosome and adhesins - Structures and function. J Struct Biol 190, 93\u2013114 (2015).","journal-title":"J Struct Biol"},{"key":"BFsrep16034_CR8","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.chom.2012.06.005","volume":"12","author":"ML Jones","year":"2012","unstructured":"Jones, M. L., Collins, M. O., Goulding, D., Choudhary, J. S. & Rayner, J. C. Analysis of protein palmitoylation reveals a pervasive role in Plasmodium development and pathogenesis. Cell Host Microbe 12, 246\u201358 (2012).","journal-title":"Cell Host Microbe"},{"key":"BFsrep16034_CR9","doi-asserted-by":"publisher","first-page":"5202","DOI":"10.1111\/j.1742-4658.2007.06056.x","volume":"274","author":"MJ Nadolski","year":"2007","unstructured":"Nadolski, M. J. & Linder, M. E. Protein lipidation. FEBS J 274, 5202\u201310 (2007).","journal-title":"FEBS J"},{"key":"BFsrep16034_CR10","doi-asserted-by":"publisher","first-page":"2488","DOI":"10.1016\/j.febslet.2012.06.011","volume":"586","author":"M Fairbank","year":"2012","unstructured":"Fairbank, M., Huang, K., El-Husseini, A. & Nabi, I. R. RING finger palmitoylation of the endoplasmic reticulum Gp78 E3 ubiquitin ligase. FEBS Lett 586, 2488\u201393 (2012).","journal-title":"FEBS Lett"},{"key":"BFsrep16034_CR11","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1038\/emboj.2012.15","volume":"31","author":"AK Lakkaraju","year":"2012","unstructured":"Lakkaraju, A. K. et al. Palmitoylated calnexin is a key component of the ribosome-translocon complex. EMBO J 31, 1823\u201335 (2012).","journal-title":"EMBO J"},{"key":"BFsrep16034_CR12","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.pt.2012.08.009","volume":"28","author":"ML Jones","year":"2012","unstructured":"Jones, M. L., Tay, C. L. & Rayner, J. C. Getting stuck in: protein palmitoylation in Plasmodium. Trends Parasitol 28, 496\u2013503 (2012).","journal-title":"Trends Parasitol"},{"key":"BFsrep16034_CR13","doi-asserted-by":"crossref","unstructured":"Corvi, M. M., Alonso, A. M. & Caballero, M. C. Protein palmitoylation and pathogenesis in apicomplexan parasites. J Biomed Biotechnol, 483969 (2012). 10.1155\/2012\/483969.","DOI":"10.1155\/2012\/483969"},{"key":"BFsrep16034_CR14","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1111\/tra.12081","volume":"14","author":"K Frenal","year":"2013","unstructured":"Frenal, K. et al. Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion. Traffic 14, 895\u2013911 (2013).","journal-title":"Traffic"},{"key":"BFsrep16034_CR15","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1194\/jlr.M800270-JLR200","volume":"50","author":"BC Jennings","year":"2009","unstructured":"Jennings, B. C. et al. 2-Bromopalmitate and 2-(2-hydroxy-5-nitro-benzylidene)-benzo[b]thiophen-3-one inhibit DHHC-mediated palmitoylation in vitro. J Lipid Res 50, 233\u201342 (2009).","journal-title":"J Lipid Res"},{"key":"BFsrep16034_CR16","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.ymeth.2006.04.013","volume":"40","author":"MD Resh","year":"2006","unstructured":"Resh, M. D. Use of analogs and inhibitors to study the functional significance of protein palmitoylation. Methods 40, 191\u20137 (2006).","journal-title":"Methods"},{"key":"BFsrep16034_CR17","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1074\/jbc.M114.598094","volume":"290","author":"J Wetzel","year":"2015","unstructured":"Wetzel, J. et al. The role of palmitoylation for protein recruitment to the inner membrane complex of the malaria parasite. J Biol Chem 290, 1712\u201328 (2015).","journal-title":"J Biol Chem"},{"key":"BFsrep16034_CR18","doi-asserted-by":"publisher","first-page":"e1003162","DOI":"10.1371\/journal.ppat.1003162","volume":"9","author":"JR Beck","year":"2013","unstructured":"Beck, J. R. et al. A Toxoplasma palmitoyl acyl transferase and the palmitoylated Armadillo Repeat protein TgARO govern apical rhoptry tethering and reveal a critical role for the rhoptries in host cell invasion but not egress. PLoS Pathog 9, e1003162 (2013).","journal-title":"PLoS Pathog"},{"key":"BFsrep16034_CR19","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.molbiopara.2012.03.006","volume":"184","author":"AM Alonso","year":"2012","unstructured":"Alonso, A. M. et al. Protein palmitoylation inhibition by 2-bromopalmitate alters gliding, host cell invasion and parasite morphology in Toxoplasma gondii. Mol Biochem Parasitol 184, 39\u201343 (2012).","journal-title":"Mol Biochem Parasitol"},{"key":"BFsrep16034_CR20","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/nchembio.1315","volume":"9","author":"MA Child","year":"2013","unstructured":"Child, M. A. et al. Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion. Nat Chem Biol 9, 651\u20136 (2013).","journal-title":"Nat Chem Biol"},{"key":"BFsrep16034_CR21","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1038\/nature01107","volume":"419","author":"L Florens","year":"2002","unstructured":"Florens, L. et al. A proteomic view of the Plasmodium falciparum life cycle. Nature 419, 520\u20136 (2002).","journal-title":"Nature"},{"key":"BFsrep16034_CR22","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1074\/mcp.M112.024505","volume":"12","author":"SE Lindner","year":"2013","unstructured":"Lindner, S. E. et al. Total and putative surface proteomics of malaria parasite salivary gland sporozoites. Mol Cell Proteomics 12, 1127\u201343 (2013).","journal-title":"Mol Cell Proteomics"},{"key":"BFsrep16034_CR23","doi-asserted-by":"publisher","first-page":"R108","DOI":"10.1186\/gb-2012-13-11-r108","volume":"13","author":"SC Oehring","year":"2012","unstructured":"Oehring, S. C. et al. Organellar proteomics reveals hundreds of novel nuclear proteins in the malaria parasite Plasmodium falciparum. Genome Biol 13, R108 (2012).","journal-title":"Genome Biol"},{"key":"BFsrep16034_CR24","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/ncomms1558","volume":"2","author":"L Solyakov","year":"2011","unstructured":"Solyakov, L. et al. Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum. Nat Commun 2, 565 (2011).","journal-title":"Nat Commun"},{"key":"BFsrep16034_CR25","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.chom.2011.09.004","volume":"10","author":"M Treeck","year":"2011","unstructured":"Treeck, M., Sanders, J. L., Elias, J. E. & Boothroyd, J. C. The phosphoproteomes of Plasmodium falciparum and Toxoplasma gondii reveal unusual adaptations within and beyond the parasites\u2019 boundaries. Cell Host Microbe 10, 410\u20139 (2011).","journal-title":"Cell Host Microbe"},{"key":"BFsrep16034_CR26","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.cell.2005.03.027","volume":"121","author":"SM Khan","year":"2005","unstructured":"Khan, S. M. et al. Proteome analysis of separated male and female gametocytes reveals novel sex-specific Plasmodium biology. Cell 121, 675\u201387 (2005).","journal-title":"Cell"},{"key":"BFsrep16034_CR27","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1126\/science.1103717","volume":"307","author":"N Hall","year":"2005","unstructured":"Hall, N. et al. A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic and proteomic analyses. Science 307, 82\u20136 (2005).","journal-title":"Science"},{"key":"BFsrep16034_CR28","doi-asserted-by":"publisher","first-page":"2492","DOI":"10.1002\/pmic.200700727","volume":"8","author":"KP Patra","year":"2008","unstructured":"Patra, K. P., Johnson, J. R., Cantin, G. T., Yates, J. R., 3rd & Vinetz, J. M. Proteomic analysis of zygote and ookinete stages of the avian malaria parasite Plasmodium gallinaceum delineates the homologous proteomes of the lethal human malaria parasite Plasmodium falciparum. Proteomics 8, 2492\u20139 (2008).","journal-title":"Proteomics"},{"key":"BFsrep16034_CR29","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1002\/pmic.200800404","volume":"9","author":"K Lal","year":"2009","unstructured":"Lal, K. et al. Characterisation of Plasmodium invasive organelles; an ookinete microneme proteome. Proteomics 9, 1142\u201351 (2009).","journal-title":"Proteomics"},{"key":"BFsrep16034_CR30","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1017\/S0031182000056481","volume":"91","author":"CJ Janse","year":"1985","unstructured":"Janse, C. J. et al. In vitro formation of ookinetes and functional maturity of Plasmodium berghei gametocytes. Parasitology 91 (Pt 1), 19\u201329 (1985).","journal-title":"Parasitology"},{"key":"BFsrep16034_CR31","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/s12915-014-0086-0","volume":"12","author":"TD Otto","year":"2014","unstructured":"Otto, T. D. et al. A comprehensive evaluation of rodent malaria parasite genomes and gene expression. BMC Biol 12, 86 (2014).","journal-title":"BMC Biol"},{"key":"BFsrep16034_CR32","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1093\/nar\/gkm1142","volume":"36","author":"JA Braks","year":"2008","unstructured":"Braks, J. A., Mair, G. R., Franke-Fayard, B., Janse, C. J. & Waters, A. P. A conserved U-rich RNA region implicated in regulation of translation in Plasmodium female gametocytes. Nucleic Acids Res 36, 1176\u201386 (2008).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep16034_CR33","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/nprot.2006.53","volume":"1","author":"CJ Janse","year":"2006","unstructured":"Janse, C. J., Ramesar, J. & Waters, A. P. High-efficiency transfection and drug selection of genetically transformed blood stages of the rodent malaria parasite Plasmodium berghei. Nat Protoc 1, 346\u201356 (2006).","journal-title":"Nat Protoc"},{"key":"BFsrep16034_CR34","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1111\/j.1462-5822.2011.01683.x","volume":"13","author":"EC Laurentino","year":"2011","unstructured":"Laurentino, E. C. et al. Experimentally controlled downregulation of the histone chaperone FACT in Plasmodium berghei reveals that it is critical to male gamete fertility. Cell Microbiol 13, 1956\u201374 (2011).","journal-title":"Cell Microbiol"},{"key":"BFsrep16034_CR35","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.molbiopara.2005.09.007","volume":"145","author":"CJ Janse","year":"2006","unstructured":"Janse, C. J. et al. High efficiency transfection of Plasmodium berghei facilitates novel selection procedures. Mol Biochem Parasitol 145, 60\u201370 (2006).","journal-title":"Mol Biochem Parasitol"},{"key":"BFsrep16034_CR36","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/0014-4894(89)90109-4","volume":"68","author":"CJ Janse","year":"1989","unstructured":"Janse, C. J. et al. Plasmodium berghei: gametocyte production, DNA content and chromosome-size polymorphisms during asexual multiplication in vivo. Exp Parasitol 68, 274\u201382 (1989).","journal-title":"Exp Parasitol"},{"key":"BFsrep16034_CR37","doi-asserted-by":"publisher","first-page":"2742","DOI":"10.1038\/nprot.2006.481","volume":"1","author":"E Scotto-Lavino","year":"2006","unstructured":"Scotto-Lavino, E., Du, G. & Frohman, M. A. 3\u2019 end cDNA amplification using classic RACE. Nat Protoc 1, 2742\u20135 (2006).","journal-title":"Nat Protoc"},{"key":"BFsrep16034_CR38","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1006\/expr.1998.4203","volume":"88","author":"AL Beetsma","year":"1998","unstructured":"Beetsma, A. L., van de Wiel, T. J., Sauerwein, R. W. & Eling, W. M. Plasmodium berghei ANKA: purification of large numbers of infectious gametocytes. Exp Parasitol 88, 69\u201372 (1998).","journal-title":"Exp Parasitol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep16034","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep16034.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep16034.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T13:36:17Z","timestamp":1672925777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep16034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,3]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,21]]}},"alternative-id":["BFsrep16034"],"URL":"https:\/\/doi.org\/10.1038\/srep16034","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,3]]},"assertion":[{"value":"14 May 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16034"}}