Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development


Autoři: Judith L. Green aff001;  Yang Wu aff001;  Vesela Encheva aff002;  Edwin Lasonder aff003;  Adchara Prommaban aff001;  Simone Kunzelmann aff005;  Evangelos Christodoulou aff005;  Munira Grainger aff001;  Ngoc Truongvan aff006;  Sebastian Bothe aff007;  Vikram Sharma aff003;  Wei Song aff008;  Irene Pinzuti aff008;  Chairat Uthaipibull aff009;  Somdet Srichairatanakool aff004;  Veronique Birault aff010;  Gordon Langsley aff011;  Hermann Schindelin aff006;  Benjamin Stieglitz aff008;  Ambrosius P. Snijders aff002;  Anthony A. Holder aff001
Působiště autorů: Malaria Parasitology Laboratory, The Francis Crick Institute, London, United Kingdom aff001;  Mass Spectrometry Proteomics, The Francis Crick Institute, London, United Kingdom aff002;  School of Biomedical Science, University of Plymouth, Plymouth, United Kingdom aff003;  Department of Biochemistry, Chiang Mai University, Chiang Mai, Thailand aff004;  Structural Biology Science Technology Platform, The Francis Crick Institute, London, United Kingdom aff005;  Rudolf Virchow Center for Experimental Biomedicine, Universität Würzburg, Würzburg, Germany aff006;  Department of Chemistry and Pharmacy, University of Würzburg, Würzburg, Germany aff007;  School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom aff008;  National Center for Genetic Engineering and Biotechnology, Khlong Luang, Thailand aff009;  Translation, The Francis Crick Institute, London, United Kingdom aff010;  Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Institut Cochin, Université Paris Descartes, Paris, France aff011
Vyšlo v časopise: Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development. PLoS Pathog 16(6): e1008640. doi:10.1371/journal.ppat.1008640
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008640

Souhrn

Ubiquitylation is a common post translational modification of eukaryotic proteins and in the human malaria parasite, Plasmodium falciparum (Pf) overall ubiquitylation increases in the transition from intracellular schizont to extracellular merozoite stages in the asexual blood stage cycle. Here, we identify specific ubiquitylation sites of protein substrates in three intraerythrocytic parasite stages and extracellular merozoites; a total of 1464 sites in 546 proteins were identified (data available via ProteomeXchange with identifier PXD014998). 469 ubiquitylated proteins were identified in merozoites compared with only 160 in the preceding intracellular schizont stage, suggesting a large increase in protein ubiquitylation associated with merozoite maturation. Following merozoite invasion of erythrocytes, few ubiquitylated proteins were detected in the first intracellular ring stage but as parasites matured through trophozoite to schizont stages the apparent extent of ubiquitylation increased. We identified commonly used ubiquitylation motifs and groups of ubiquitylated proteins in specific areas of cellular function, for example merozoite pellicle proteins involved in erythrocyte invasion, exported proteins, and histones. To investigate the importance of ubiquitylation we screened ubiquitin pathway inhibitors in a parasite growth assay and identified the ubiquitin activating enzyme (UBA1 or E1) inhibitor MLN7243 (TAK-243) to be particularly effective. This small molecule was shown to be a potent inhibitor of recombinant PfUBA1, and a structural homology model of MLN7243 bound to the parasite enzyme highlights avenues for the development of P. falciparum specific inhibitors. We created a genetically modified parasite with a rapamycin-inducible functional deletion of uba1; addition of either MLN7243 or rapamycin to the recombinant parasite line resulted in the same phenotype, with parasite development blocked at the schizont stage. Nuclear division and formation of intracellular structures was interrupted. These results indicate that the intracellular target of MLN7243 is UBA1, and this activity is essential for the final differentiation of schizonts to merozoites.

Klíčová slova:

Malaria – Malarial parasites – Merozoites – Parasitic diseases – Parasitic life cycles – Plasmodium – Red blood cells – Sequence motif analysis


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