PfAP2-G2 Is Associated to Production and Maturation of Gametocytes in Regulating the Expression of

Overview

Journal Front Microbiol

Specialty Microbiology

Date 2021 Feb 4

PMID 33537025

Citations 9

Authors

Yaozheng Xu

Dan Qiao

Yuhao Wen

Yifei Bi

Yuxi Chen

Zhenghui Huang

Liwang Cui

Jian Guo

Yaming Cao

Affiliations

Soon will be listed here.

Abstract

Gametocyte is the sole form of the which is transmissible to the mosquito vector. Here, we report that an Apicomplexan Apetala2 (ApiAP2) family transcription factor, PfAP2-G2 (Pf3D7_1408200), plays a role in the development of gametocytes in by regulating the expression of . Reverse transcriptase-quantitative PCR (RT-qPCR) analysis showed that was highly expressed in the ring stage. Indirect immunofluorescence assay showed nuclear localization of PfAP2-G2 in asexual stages. The knockout of led to a ~95% decrease in the number of mature gametocytes with a more substantial influence on the production and maturation of the male gametocytes, resulting in a higher female/male gametocyte ratio. To test the mechanism of this phenotype, RNA-seq and RT-qPCR showed that disruption of led to the down-regulation of male development gene-1 () in asexual stages. We further found that PfAP2-G2 was enriched at the transcriptional start site (TSS) of by chromatin immunoprecipitation and qPCR assay in both ring stage and schizont stage, which demonstrated that is one of the targets of PfAP2-G2. In addition, RT-qPCR also showed that PfAP2-G (Pf3D7_1222600), the master regulator for sexual commitment, was also down-regulated in the PfAP2-G2 knockout parasites in the schizont stage, but no change in the ring stage. This phenomenon suggested that PfAP2-G2 played a role at the asexual stage for the development of parasite gametocytes and warrants further investigations in regulatory pathways of PfAP2-G2.

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References

De Silva E, Gehrke A, Olszewski K, Leon I, Chahal J, Bulyk M . Specific DNA-binding by apicomplexan AP2 transcription factors. Proc Natl Acad Sci U S A. 2008; 105(24):8393-8. PMC: 2423414. DOI: 10.1073/pnas.0801993105. View

Sinha A, Hughes K, Modrzynska K, Otto T, Pfander C, Dickens N . A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. Nature. 2014; 507(7491):253-257. PMC: 4105895. DOI: 10.1038/nature12970. View

Furuya T, Mu J, Hayton K, Liu A, Duan J, Nkrumah L . Disruption of a Plasmodium falciparum gene linked to male sexual development causes early arrest in gametocytogenesis. Proc Natl Acad Sci U S A. 2005; 102(46):16813-8. PMC: 1277966. DOI: 10.1073/pnas.0501858102. View

Martins R, MacPherson C, Claes A, Scheidig-Benatar C, Sakamoto H, Yam X . An ApiAP2 member regulates expression of clonally variant genes of the human malaria parasite Plasmodium falciparum. Sci Rep. 2017; 7(1):14042. PMC: 5656681. DOI: 10.1038/s41598-017-12578-y. View

Schwank S, Sutherland C, Drakeley C . Promiscuous expression of α-tubulin II in maturing male and female Plasmodium falciparum gametocytes. PLoS One. 2011; 5(12):e14470. PMC: 3012678. DOI: 10.1371/journal.pone.0014470. View

Henry N, Serme S, Siciliano G, Sombie S, Diarra A, Sagnon N . Biology of Plasmodium falciparum gametocyte sex ratio and implications in malaria parasite transmission. Malar J. 2019; 18(1):70. PMC: 6417185. DOI: 10.1186/s12936-019-2707-0. View

Josling G, Llinas M . Sexual development in Plasmodium parasites: knowing when it's time to commit. Nat Rev Microbiol. 2015; 13(9):573-87. DOI: 10.1038/nrmicro3519. View

Sierra-Miranda M, Vembar S, Delgadillo D, Avila-Lopez P, Herrera-Solorio A, Lozano Amado D . PfAP2Tel, harbouring a non-canonical DNA-binding AP2 domain, binds to Plasmodium falciparum telomeres. Cell Microbiol. 2017; 19(9). DOI: 10.1111/cmi.12742. View

Iwanaga S, Kaneko I, Kato T, Yuda M . Identification of an AP2-family protein that is critical for malaria liver stage development. PLoS One. 2012; 7(11):e47557. PMC: 3492389. DOI: 10.1371/journal.pone.0047557. View

10.

Pertea M, Pertea G, Antonescu C, Chang T, Mendell J, Salzberg S . StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015; 33(3):290-5. PMC: 4643835. DOI: 10.1038/nbt.3122. View

11.

Bischoff E, Vaquero C . In silico and biological survey of transcription-associated proteins implicated in the transcriptional machinery during the erythrocytic development of Plasmodium falciparum. BMC Genomics. 2010; 11:34. PMC: 2821373. DOI: 10.1186/1471-2164-11-34. View

12.

Kim D, Langmead B, Salzberg S . HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015; 12(4):357-60. PMC: 4655817. DOI: 10.1038/nmeth.3317. View

13.

Guinet F, DVORAK J, Fujioka H, Keister D, Muratova O, Kaslow D . A developmental defect in Plasmodium falciparum male gametogenesis. J Cell Biol. 1996; 135(1):269-78. PMC: 2121010. DOI: 10.1083/jcb.135.1.269. View

14.

Campbell T, De Silva E, Olszewski K, Elemento O, Llinas M . Identification and genome-wide prediction of DNA binding specificities for the ApiAP2 family of regulators from the malaria parasite. PLoS Pathog. 2010; 6(10):e1001165. PMC: 2965767. DOI: 10.1371/journal.ppat.1001165. View

15.

Amoah L, Acquah F, Nyarko P, Cudjoe E, Donu D, Ayanful-Torgby R . Comparative analysis of asexual and sexual stage Plasmodium falciparum development in different red blood cell types. Malar J. 2020; 19(1):200. PMC: 7275330. DOI: 10.1186/s12936-020-03275-9. View

16.

Ciuffreda L, Zoiku F, Quashie N, Ranford-Cartwright L . Estimation of parasite age and synchrony status in Plasmodium falciparum infections. Sci Rep. 2020; 10(1):10925. PMC: 7331735. DOI: 10.1038/s41598-020-67817-6. View

17.

Santos J, Josling G, Ross P, Joshi P, Orchard L, Campbell T . Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor. Cell Host Microbe. 2017; 21(6):731-741.e10. PMC: 5855115. DOI: 10.1016/j.chom.2017.05.006. View

18.

Josling G, Williamson K, Llinas M . Regulation of Sexual Commitment and Gametocytogenesis in Malaria Parasites. Annu Rev Microbiol. 2018; 72:501-519. PMC: 7164540. DOI: 10.1146/annurev-micro-090817-062712. View

19.

Flueck C, Bartfai R, Niederwieser I, Witmer K, Alako B, Moes S . A major role for the Plasmodium falciparum ApiAP2 protein PfSIP2 in chromosome end biology. PLoS Pathog. 2010; 6(2):e1000784. PMC: 2829057. DOI: 10.1371/journal.ppat.1000784. View

20.

Kafsack B, Rovira-Graells N, Clark T, Bancells C, Crowley V, Campino S . A transcriptional switch underlies commitment to sexual development in malaria parasites. Nature. 2014; 507(7491):248-52. PMC: 4040541. DOI: 10.1038/nature12920. View