DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages
-
Published:2023-10-26
Issue:11
Volume:8
Page:2154-2169
-
ISSN:2058-5276
-
Container-title:Nature Microbiology
-
language:en
-
Short-container-title:Nat Microbiol
Author:
Subudhi Amit KumarORCID, Green Judith L.ORCID, Satyam Rohit, Salunke Rahul P., Lenz ToddORCID, Shuaib MuhammadORCID, Isaioglou IoannisORCID, Abel Steven, Gupta MohitORCID, Esau Luke, Mourier TobiasORCID, Nugmanova Raushan, Mfarrej SaraORCID, Shivapurkar Rupali, Stead Zenaida, Rached Fathia BenORCID, Ostwal Yogesh, Sougrat Rachid, Dada Ashraf, Kadamany Abdullah Fuaad, Fischle Wolfgang, Merzaban JasmeenORCID, Knuepfer EllenORCID, Ferguson David J. P.ORCID, Gupta IshaanORCID, Le Roch Karine G.ORCID, Holder Anthony A.ORCID, Pain ArnabORCID
Abstract
AbstractMalaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress. Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion. We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.
Funder
King Abdullah University of Science and Technology Division of Intramural Research, National Institute of Allergy and Infectious Diseases UC | University of California, Riverside Wellcome Trust
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Microbiology (medical),Genetics,Applied Microbiology and Biotechnology,Immunology,Microbiology
Reference70 articles.
1. Toenhake, C. G. et al. Chromatin accessibility-based characterization of the gene regulatory network underlying plasmodium falciparum blood-stage development. Cell Host Microbe 23, 557–569 (2018). 2. Cortes, A. & Deitsch, K. W. Malaria epigenetics. Cold Spring Harb. Perspect. Med. 7, a025528 (2017). 3. Iwanaga, S., Kaneko, I., Kato, T. & Yuda, M. Identification of an AP2-family protein that is critical for malaria liver stage development. PLoS ONE 7, e47557 (2012). 4. Kafsack, B. F. et al. A transcriptional switch underlies commitment to sexual development in malaria parasites. Nature 507, 248–252 (2014). 5. Painter, H. J., Campbell, T. L. & Llinas, M. The Apicomplexan AP2 family: integral factors regulating Plasmodium development. Mol. Biochem. Parasitol. 176, 1–7 (2011).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|