The systematic functional analysis of plasmodium protein kinases identifies essential regulators of mosquito transmission
KAUST DepartmentComputational Bioscience Research Center (CBRC)
MetadataShow full item record
AbstractAlthough eukaryotic protein kinases (ePKs) contribute to many cellular processes, only three Plasmodium falciparum ePKs have thus far been identified as essential for parasite asexual blood stage development. To identify pathways essential for parasite transmission between their mammalian host and mosquito vector, we undertook a systematic functional analysis of ePKs in the genetically tractable rodent parasite Plasmodium berghei. Modeling domain signatures of conventional ePKs identified 66 putative Plasmodium ePKs. Kinomes are highly conserved between Plasmodium species. Using reverse genetics, we show that 23 ePKs are redundant for asexual erythrocytic parasite development in mice. Phenotyping mutants at four life cycle stages in Anopheles stephensi mosquitoes revealed functional clusters of kinases required for sexual development and sporogony. Roles for a putative SR protein kinase (SRPK) in microgamete formation, a conserved regulator of clathrin uncoating (GAK) in ookinete formation, and a likely regulator of energy metabolism (SNF1/KIN) in sporozoite development were identified. 2010 Elsevier Inc.
CitationTewari R, Straschil U, Bateman A, Böhme U, Cherevach I, et al. (2010) The Systematic Functional Analysis of Plasmodium Protein Kinases Identifies Essential Regulators of Mosquito Transmission. Cell Host and Microbe 8: 377-387. doi:10.1016/j.chom.2010.09.006.
JournalCell Host & Microbe
PubMed Central IDPMC2977076
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as Open Access funded by Wellcome Trust
- Type II fatty acid biosynthesis is essential for Plasmodium falciparum sporozoite development in the midgut of Anopheles mosquitoes.
- Authors: van Schaijk BC, Kumar TR, Vos MW, Richman A, van Gemert GJ, Li T, Eappen AG, Williamson KC, Morahan BJ, Fishbaugher M, Kennedy M, Camargo N, Khan SM, Janse CJ, Sim KL, Hoffman SL, Kappe SH, Sauerwein RW, Fidock DA, Vaughan AM
- Issue date: 2014 May
- Inhibitor of cysteine proteases is critical for motility and infectivity of Plasmodium sporozoites.
- Authors: Boysen KE, Matuschewski K
- Issue date: 2013 Nov 26
- Genetic Characterization of Plasmodium Putative Pantothenate Kinase Genes Reveals Their Essential Role in Malaria Parasite Transmission to the Mosquito.
- Authors: Hart RJ, Cornillot E, Abraham A, Molina E, Nation CS, Ben Mamoun C, Aly AS
- Issue date: 2016 Sep 20
- The Puf-family RNA-binding protein Puf2 controls sporozoite conversion to liver stages in the malaria parasite.
- Authors: Müller K, Matuschewski K, Silvie O
- Issue date: 2011
- Total and putative surface proteomics of malaria parasite salivary gland sporozoites.
- Authors: Lindner SE, Swearingen KE, Harupa A, Vaughan AM, Sinnis P, Moritz RL, Kappe SH
- Issue date: 2013 May
Showing items related by title, author, creator and subject.
Transition of Plasmodium sporozoites into liver stage-like forms is regulated by the RNA binding protein PumilioGomes-Santos, Carina S. S.; Braks, Joanna; Prudêncio, Miguel; Carret, Céline; Gomes, Ana Rita; Pain, Arnab; Feltwell, Theresa; Khan, Shahid; Waters, Andrew; Janse, Chris; Mair, Gunnar R.; Mota, Maria M. (Public Library of Science (PLoS), 2011-05-19)Many eukaryotic developmental and cell fate decisions that are effected post-transcriptionally involve RNA binding proteins as regulators of translation of key mRNAs. In malaria parasites (Plasmodium spp.), the development of round, non-motile and replicating exo-erythrocytic liver stage forms from slender, motile and cell-cycle arrested sporozoites is believed to depend on environmental changes experienced during the transmission of the parasite from the mosquito vector to the vertebrate host. Here we identify a Plasmodium member of the RNA binding protein family PUF as a key regulator of this transformation. In the absence of Pumilio-2 (Puf2) sporozoites initiate EEF development inside mosquito salivary glands independently of the normal transmission-associated environmental cues. Puf2- sporozoites exhibit genome-wide transcriptional changes that result in loss of gliding motility, cell traversal ability and reduction in infectivity, and, moreover, trigger metamorphosis typical of early Plasmodium intra-hepatic development. These data demonstrate that Puf2 is a key player in regulating sporozoite developmental control, and imply that transformation of salivary gland-resident sporozoites into liver stage-like parasites is regulated by a post-transcriptional mechanism. 2011 Gomes-Santos et al.
Characterization and gene expression analysis of the cir multi-gene family of plasmodium chabaudi chabaudi (AS)Lawton, Jennifer; Brugat, Thibaut; Yan, Yam Xue; Reid, Adam James; Böhme, Ulrike; Otto, Thomas Dan; Pain, Arnab; Jackson, Andrew; Berriman, Matthew; Cunningham, Deirdre; Preiser, Peter; Langhorne, Jean (Springer Nature, 2012-03-29)Background: The pir genes comprise the largest multi-gene family in Plasmodium, with members found in P. vivax, P. knowlesi and the rodent malaria species. Despite comprising up to 5% of the genome, little is known about the functions of the proteins encoded by pir genes. P. chabaudi causes chronic infection in mice, which may be due to antigenic variation. In this model, pir genes are called cirs and may be involved in this mechanism, allowing evasion of host immune responses. In order to fully understand the role(s) of CIR proteins during P. chabaudi infection, a detailed characterization of the cir gene family was required.Results: The cir repertoire was annotated and a detailed bioinformatic characterization of the encoded CIR proteins was performed. Two major sub-families were identified, which have been named A and B. Members of each sub-family displayed different amino acid motifs, and were thus predicted to have undergone functional divergence. In addition, the expression of the entire cir repertoire was analyzed via RNA sequencing and microarray. Up to 40% of the cir gene repertoire was expressed in the parasite population during infection, and dominant cir transcripts could be identified. In addition, some differences were observed in the pattern of expression between the cir subgroups at the peak of P. chabaudi infection. Finally, specific cir genes were expressed at different time points during asexual blood stages.Conclusions: In conclusion, the large number of cir genes and their expression throughout the intraerythrocytic cycle of development indicates that CIR proteins are likely to be important for parasite survival. In particular, the detection of dominant cir transcripts at the peak of P. chabaudi infection supports the idea that CIR proteins are expressed, and could perform important functions in the biology of this parasite. Further application of the methodologies described here may allow the elucidation of CIR sub-family A and B protein functions, including their contribution to antigenic variation and immune evasion. 2012 Lawton et al; licensee BioMed Central Ltd.
Targeted disruption of py235ebp-1: Invasion of erythrocytes by Plasmodium yoelii using an alternative py235 erythrocyte binding proteinOgun, Solabomi A.; Tewari, Rita; Otto, Thomas D.; Howell, Steven A.; Knuepfer, Ellen; Cunningham, Deirdre A.; Xu, Zhengyao; Pain, Arnab; Holder, Anthony A. (Public Library of Science (PLoS), 2011-02-17)Plasmodium yoelii YM asexual blood stage parasites express multiple members of the py235 gene family, part of the super-family of genes including those coding for Plasmodium vivax reticulocyte binding proteins and Plasmodium falciparum RH proteins. We previously identified a Py235 erythrocyte binding protein (Py235EBP-1, encoded by the PY01365 gene) that is recognized by protective mAb 25.77. Proteins recognized by a second protective mAb 25.37 have been identified by mass spectrometry and are encoded by two genes, PY01185 and PY05995/PY03534. We deleted the PY01365 gene and examined the phenotype. The expression of the members of the py235 family in both the WT and gene deletion parasites was measured by quantitative RT-PCR and RNA-Seq. py235ebp-1 expression was undetectable in the knockout parasite, but transcription of other members of the family was essentially unaffected. The knockout parasites continued to react with mAb 25.77; and the 25.77-binding proteins in these parasites were the PY01185 and PY05995/PY03534 products. The PY01185 product was also identified as erythrocyte binding. There was no clear change in erythrocyte invasion profile suggesting that the PY01185 gene product (designated PY235EBP-2) is able to fulfill the role of EBP-1 by serving as an invasion ligand although the molecular details of its interaction with erythrocytes have not been examined. The PY01365, PY01185, and PY05995/PY03534 genes are part of a distinct subset of the py235 family. In P. falciparum, the RH protein genes are under epigenetic control and expression correlates with binding to distinct erythrocyte receptors and specific invasion pathways, whereas in P. yoelii YM all the genes are expressed and deletion of one does not result in upregulation of another. We propose that simultaneous expression of multiple Py235 ligands enables invasion of a wide range of host erythrocytes even in the presence of antibodies to one or more of the proteins and that this functional redundancy at the protein level gives the parasite phenotypic plasticity in the absence of differences in gene expression. © 2011 Ogun et al.