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Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation

Kyle Tretina 1 Malak Haidar 2, 3 Sally Madsen-Bouterse 4 Takaya Sakura 2, 3 Sara Mfarrej 5 Lindsay Fry 4, 6 Marie Chaussepied 2, 3, 7 Arnab Pain 5 Donald Knowles 4 Vishvanath Nene 8 Doron Ginsberg 7, 9 Claudia Daubenberger 10, 11 Richard Bishop 4 Gordon Langsley 2, 3 Joana Silva 1, *
* Corresponding author
1 University of Maryland School of Medicine
2 Laboratoire de Biologie Comparative des Apicomplexes [Paris]
3 IC UM3 (UMR 8104 / U1016) - Institut Cochin
4 WSU - Washington State University
5 KAUST - King Abdullah University of Science and Technology
6 United States Department of Agriculture - USDA (USA)
7 Weizmann Institute of Science
8 ILRI - International Livestock Research Institute [Nairobi]
9 Bar-Ilan University [Israël]
10 Swiss Tropical and Public Health Institute [Basel]
11 Unibas - University of Basel
Abstract : Intracellular pathogens have evolved intricate mechanisms to subvert host cell signaling pathways and ensure their own propagation. A lineage of the protozoan parasite genus Theileria infects bovine leukocytes and induces their uncontrolled proliferation causing a leukemia-like disease. Given the importance of E2F transcription factors in mammalian cell cycle regulation, we investigated the role of E2F signaling in Theileria-induced host cell proliferation. Using comparative genomics and surface plasmon resonance, we identified parasite-derived peptides that have the sequence-specific ability to increase E2F signaling by binding E2F negative regulator Retinoblastoma-1 (RB). Using these peptides as a tool to probe host E2F signaling, we show that the disruption of RB complexes ex vivo leads to activation of E2F-driven transcription and increased leukocyte proliferation in an infection-dependent manner. This result is consistent with existing models and, together, they support a critical role of E2F signaling for Theileria-induced host cell proliferation, and its potential direct manipulation by one or more parasite proteins.
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Submitted on : Thursday, March 12, 2020 - 1:26:30 PM
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Kyle Tretina, Malak Haidar, Sally Madsen-Bouterse, Takaya Sakura, Sara Mfarrej, et al.. Theileria parasites subvert E2F signaling to stimulate leukocyte proliferation. Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.3982. ⟨10.1038/s41598-020-60939-x⟩. ⟨inserm-02506492⟩

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