A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium

Abhinav Sinha, Katie R. Hughes, Katarzyna K. Modrzynska, Thomas D. Otto, Claudia Pfander, Nicholas J. Dickens, Agnieszka A. Religa, Ellen Bushell, Anne L. Graham, Rachael Cameron, Bjorn F.C. Kafsack, April E. Williams, Manuel Llinás, Matthew Berriman, Oliver Billker, Andrew P. Waters

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes. The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in Plasmodium berghei, a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA-143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA-103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.

Original languageEnglish (US)
Pages (from-to)253-257
Number of pages5
JournalNature
Volume507
Issue number7491
DOIs
StatePublished - Jan 1 2014

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Sexual Development
Plasmodium
DNA-Binding Proteins
Parasites
Malaria
Plasmodium berghei
Gene Deletion
Culicidae
Genes
Rodentia
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Sinha, A., Hughes, K. R., Modrzynska, K. K., Otto, T. D., Pfander, C., Dickens, N. J., ... Waters, A. P. (2014). A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. Nature, 507(7491), 253-257. https://doi.org/10.1038/nature12970
Sinha, Abhinav ; Hughes, Katie R. ; Modrzynska, Katarzyna K. ; Otto, Thomas D. ; Pfander, Claudia ; Dickens, Nicholas J. ; Religa, Agnieszka A. ; Bushell, Ellen ; Graham, Anne L. ; Cameron, Rachael ; Kafsack, Bjorn F.C. ; Williams, April E. ; Llinás, Manuel ; Berriman, Matthew ; Billker, Oliver ; Waters, Andrew P. / A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. In: Nature. 2014 ; Vol. 507, No. 7491. pp. 253-257.
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Sinha, A, Hughes, KR, Modrzynska, KK, Otto, TD, Pfander, C, Dickens, NJ, Religa, AA, Bushell, E, Graham, AL, Cameron, R, Kafsack, BFC, Williams, AE, Llinás, M, Berriman, M, Billker, O & Waters, AP 2014, 'A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium', Nature, vol. 507, no. 7491, pp. 253-257. https://doi.org/10.1038/nature12970

A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. / Sinha, Abhinav; Hughes, Katie R.; Modrzynska, Katarzyna K.; Otto, Thomas D.; Pfander, Claudia; Dickens, Nicholas J.; Religa, Agnieszka A.; Bushell, Ellen; Graham, Anne L.; Cameron, Rachael; Kafsack, Bjorn F.C.; Williams, April E.; Llinás, Manuel; Berriman, Matthew; Billker, Oliver; Waters, Andrew P.

In: Nature, Vol. 507, No. 7491, 01.01.2014, p. 253-257.

Research output: Contribution to journalArticle

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AU - Sinha, Abhinav

AU - Hughes, Katie R.

AU - Modrzynska, Katarzyna K.

AU - Otto, Thomas D.

AU - Pfander, Claudia

AU - Dickens, Nicholas J.

AU - Religa, Agnieszka A.

AU - Bushell, Ellen

AU - Graham, Anne L.

AU - Cameron, Rachael

AU - Kafsack, Bjorn F.C.

AU - Williams, April E.

AU - Llinás, Manuel

AU - Berriman, Matthew

AU - Billker, Oliver

AU - Waters, Andrew P.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes. The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in Plasmodium berghei, a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA-143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA-103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.

AB - Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes. The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in Plasmodium berghei, a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA-143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA-103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.

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Sinha A, Hughes KR, Modrzynska KK, Otto TD, Pfander C, Dickens NJ et al. A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. Nature. 2014 Jan 1;507(7491):253-257. https://doi.org/10.1038/nature12970