{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T03:48:31Z","timestamp":1780544911115,"version":"3.54.1"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T00:00:00Z","timestamp":1649030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p><jats:italic>Plasmodium falciparum<\/jats:italic> sexual stage gametocytes are critical for parasite transmission from the human host to the mosquito vector. Mature gametocytes generate fertile male (micro-) or female (macro-) gametes upon activation inside the mosquito midgut. While a number of parasite genes have been described that are critical for <jats:italic>P. falciparum<\/jats:italic> gametogenesis and fertility, no parasite gene has been shown to have a unique function in macrogametes. The genome of <jats:italic>P. falciparum<\/jats:italic> encodes numerous RNA-binding proteins. We identified a novel protein containing a putative RNA-binding domain, which we named Macrogamete-Contributed Factor Essential for Transmission (MaCFET). This protein is expressed in the asexual and sexual stages. Parasites that carry a deletion of <jats:italic>MaCFET<\/jats:italic> (<jats:italic>Pfmacfet\u00af<\/jats:italic>), developed normally as asexual stages, indicating that its function is not essential for the asexual proliferation of the parasite <jats:italic>in vitro<\/jats:italic>. Furthermore, <jats:italic>Pfmacfet\u00af<\/jats:italic> male and female gametocytes developed normally and underwent activation to form microgametes and macrogametes. However, by utilizing genetic crosses, we demonstrate that <jats:italic>Pfmacfet\u00af<\/jats:italic> parasites suffer a complete female-specific defect in successful fertilization. Therefore, <jats:italic>Pf<\/jats:italic>MaCFET is a critical female-contributed factor for parasite transmission to the mosquito. Based on its putative RNA-binding properties, <jats:italic>Pf<\/jats:italic>MaCFET might be in involved in the regulation of mRNAs that encode female-specific functions for fertilization or female-contributed factors needed post fertilization.<\/jats:p>","DOI":"10.3389\/fcell.2022.825247","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T06:46:59Z","timestamp":1649054819000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["A Putative Plasmodium RNA-Binding Protein Plays a Critical Role in Female Gamete Fertility and Parasite Transmission to the Mosquito Vector"],"prefix":"10.3389","volume":"10","author":[{"given":"Sudhir","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biley A.","family":"Abatiyow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meseret T.","family":"Haile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenza M. Z.","family":"Oualim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda S.","family":"Leeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M.","family":"Vaughan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan H.I.","family":"Kappe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.1038\/s41598-018-21801-3","article-title":"Sequential Membrane Rupture and Vesiculation during Plasmodium Berghei Gametocyte Egress from the Red Blood Cell","volume":"8","author":"Andreadaki","year":"2018","journal-title":"Sci. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/s0092-8674(04)00449-0","article-title":"Calcium and a Calcium-dependent Protein Kinase Regulate Gamete Formation and Mosquito Transmission in a Malaria Parasite","volume":"117","author":"Billker","year":"2004","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/32667","article-title":"Identification of Xanthurenic Acid as the Putative Inducer of Malaria Development in the Mosquito","volume":"392","author":"Billker","year":"1998","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1083\/jcb.200801183","article-title":"Protection of Specific Maternal Messenger RNAs by the P Body Protein CGH-1 (Dhh1\/RCK) during Caenorhabditis elegans Oogenesis","volume":"182","author":"Boag","year":"2008","journal-title":"J. Cel. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s13059-016-1014-0","article-title":"The mRNA-Bound Proteome of the Human Malaria Parasite Plasmodium Falciparum","volume":"17","author":"Bunnik","year":"2016","journal-title":"Genome Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.3389\/fimmu.2018.01094","article-title":"Uncovering the Role of RNA-Binding Proteins in Gene Expression in the Immune System","volume":"9","author":"D\u00edaz-Mu\u00f1oz","year":"2018","journal-title":"Front. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.pt.2015.08.002","article-title":"Commit and Transmit: Molecular Players in Plasmodium Sexual Development and Zygote Differentiation","volume":"31","author":"Guttery","year":"2015","journal-title":"Trends Parasitology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1126\/science.1184785","article-title":"That Was Then but This Is Now: Malaria Research in the Time of an Eradication Agenda","volume":"328","author":"Kappe","year":"2010","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","first-page":"a002683","DOI":"10.1101\/cshperspect.a002683","article-title":"Molecular Regulation of the Mitosis\/meiosis Decision in Multicellular Organisms","volume":"3","author":"Kimble","year":"2011","journal-title":"Cold Spring Harbor Perspect. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e0257521","DOI":"10.1128\/mbio.02575-21","article-title":"Plasmodium Falciparum Calcium-dependent Protein Kinase 4 Is Critical for Male Gametogenesis and Transmission to the Mosquito Vector","volume":"12","author":"Kumar","year":"2021","journal-title":"mBio"},{"key":"B11","doi-asserted-by":"publisher","first-page":"6087","DOI":"10.1093\/nar\/gkw536","article-title":"Integrated Transcriptomic and Proteomic Analyses ofP. Falciparumgametocytes: Molecular Insight into Sex-specific Processes and Translational Repression","volume":"44","author":"Lasonder","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e51660","DOI":"10.15252\/embr.202051660","article-title":"Plasmodium Transcription Repressor AP2-O3 Regulates Sex-specific Identity of Gene Expression in Female Gametocytes","volume":"22","author":"Li","year":"2021","journal-title":"EMBO Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1186\/1471-2164-12-587","article-title":"Directional Gene Expression and Antisense Transcripts in Sexual and Asexual Stages of Plasmodium Falciparum","volume":"12","author":"L\u00f3pez-Barrag\u00e1n","year":"2011","journal-title":"BMC genomics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1126\/science.1125129","article-title":"Regulation of Sexual Development of Plasmodium by Translational Repression","volume":"313","author":"Mair","year":"2006","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e1000767","DOI":"10.1371\/journal.ppat.1000767","article-title":"Universal Features of post-transcriptional Gene Regulation Are Critical for Plasmodium Zygote Development","volume":"6","author":"Mair","year":"2010","journal-title":"Plos Pathog."},{"key":"B16","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1074\/mcp.m116.061804","article-title":"Sex-Specific Biology of the Human Malaria Parasite Revealed from the Proteomes of Mature Male and Female Gametocytes","volume":"16","author":"Miao","year":"2017","journal-title":"Mol. Cell Proteomics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e1642","DOI":"10.1002\/wrna.1642","article-title":"Germ Cell Ribonucleoprotein Granules in Different Clades of Life: From Insects to Mammals","volume":"12","author":"Mukherjee","year":"2021","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"B18","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1530\/rep-11-0257","article-title":"RNA-binding Proteins, RNA Granules, and Gametes: Is unity Strength?","volume":"142","author":"Nguyen-Chi","year":"2011","journal-title":"Reproduction (Cambridge, England)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1590\/1678-4685-gmb-2016-0258","article-title":"RNA-binding Proteins and Their Role in the Regulation of Gene Expression in Trypanosoma Cruzi and Saccharomyces cerevisiae","volume":"40","author":"Oliveira","year":"2017","journal-title":"Genet. Mol. Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/sqb.2008.73.057","article-title":"Regulating Gene Expression in the Drosophila Germ Line","volume":"73","author":"Rangan","year":"2008","journal-title":"Cold Spring Harbor symposia quantitative Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1186\/s12864-015-2092-1","article-title":"A Bioinformatic Survey of RNA-Binding Proteins in Plasmodium","volume":"16","author":"Reddy","year":"2015","journal-title":"BMC genomics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1017\/s0031182000048861","article-title":"Cytology and Kinetics of Microgametogenesis and Fertilization inPlasmodium Yoelii Nigeriensis","volume":"70","author":"Sinden","year":"1975","journal-title":"Parasitology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/s0065-308x(08)60462-5","article-title":"Sexual Development of Malarial Parasites","volume":"22","author":"Sinden","year":"1983","journal-title":"Adv. Parasitol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/s42003-020-01123-9","article-title":"Structure and Function of a Malaria Transmission Blocking Vaccine Targeting Pfs230 and Pfs230-Pfs48\/45 Proteins","volume":"3","author":"Singh","year":"2020","journal-title":"Commun. Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1126\/science.1138236","article-title":"Regulation of the Oocyte-To-Zygote Transition","volume":"316","author":"Stitzel","year":"2007","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/j.pt.2018.12.001","article-title":"Gametocyte Sex Ratio: The Key to Understanding Plasmodium Falciparum Transmission?","volume":"35","author":"Tadesse","year":"2019","journal-title":"Trends Parasitology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.gene.2013.03.063","article-title":"Plasmodium Falciparum DOZI, an RNA Helicase Interacts with eIF4E","volume":"522","author":"Tarique","year":"2013","journal-title":"Gene"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e61426","DOI":"10.3791\/61426","article-title":"Plasmodium Falciparum Gametocyte Culture and Mosquito Infection through Artificial Membrane Feeding","volume":"161","author":"Tripathi","year":"2020","journal-title":"J. visualized experiments : JoVE"},{"key":"B29","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1186\/s12864-019-6322-9","article-title":"Hierarchical Transcriptional Control Regulates Plasmodium Falciparum Sexual Differentiation","volume":"20","author":"van Biljon","year":"2019","journal-title":"BMC genomics"},{"key":"B30","doi-asserted-by":"publisher","first-page":"a002774","DOI":"10.1101\/cshperspect.a002774","article-title":"RNA Granules in Germ Cells","volume":"3","author":"Voronina","year":"2011","journal-title":"Cold Spring Harb Perspect. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1111\/mmi.14334","article-title":"Female\u2010specific Gene Regulation in Malaria Parasites by an AP2\u2010family Transcription Factor","volume":"113","author":"Yuda","year":"2020","journal-title":"Mol. Microbiol."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.825247\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T11:43:46Z","timestamp":1649331826000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.825247\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,4]]},"references-count":31,"alternative-id":["10.3389\/fcell.2022.825247"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.825247","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,4]]},"article-number":"825247"}}