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

157 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.

LanguageEnglish
Pages253–257
Number of pages5
JournalNature
Volume507
Issue number7491
DOIs
Publication statusPublished - 13 Mar 2014

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DNA-Binding Proteins
Genes
Gene encoding
Blood
Feedback
Parasites
Proteins

Keywords

  • animals
  • culicidae
  • DNA-binding proteins
  • physiological feedback
  • female
  • gene expression regulation
  • germ cells
  • malaria
  • male
  • mutation
  • plasmodium berghei
  • protein transport
  • protozoan proteins
  • asexual reproduction
  • sexual development
  • genetic transcription

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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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.",
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author = "Abhinav Sinha and Hughes, {Katie R.} and Modrzynska, {Katarzyna K.} and Otto, {Thomas D.} and Claudia Pfander and Dickens, {Nicholas J.} and Religa, {Agnieszka A.} and Ellen Bushell and Graham, {Anne L.} and Rachael Cameron and Kafsack, {Bjorn F. C.} and Williams, {April E.} and Manuel Llin{\'a}s and Matthew Berriman and Oliver Billker and Waters, {Andrew P.}",
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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, 13.03.2014, p. 253–257.

Research output: Contribution to journalArticle

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T1 - A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium

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 - 2014/3/13

Y1 - 2014/3/13

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.

KW - animals

KW - culicidae

KW - DNA-binding proteins

KW - physiological feedback

KW - female

KW - gene expression regulation

KW - germ cells

KW - malaria

KW - male

KW - mutation

KW - plasmodium berghei

KW - protein transport

KW - protozoan proteins

KW - asexual reproduction

KW - sexual development

KW - genetic transcription

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DO - 10.1038/nature12970

M3 - Article

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EP - 257

JO - Nature

T2 - Nature

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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 Mar 13;507(7491):253–257. https://doi.org/10.1038/nature12970