Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Program in Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Sci Rep. 2020 Mar 4;10(1):3982. doi: 10.1038/s41598-020-60939-x.
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.
细胞内病原体进化出了复杂的机制来颠覆宿主细胞信号通路并确保自身的繁殖。一类原虫寄生虫属泰勒虫感染牛白细胞并诱导其不受控制的增殖，导致类似白血病的疾病。鉴于 E2F 转录因子在哺乳动物细胞周期调控中的重要性，我们研究了 E2F 信号在泰勒虫诱导的宿主细胞增殖中的作用。通过比较基因组学和表面等离子体共振，我们鉴定出寄生虫衍生的肽具有通过结合 E2F 负调节剂视网膜母细胞瘤-1（RB）来增加 E2F 信号的序列特异性能力。我们使用这些肽作为工具来探测宿主 E2F 信号，结果表明，体外破坏 RB 复合物会导致 E2F 驱动的转录激活，并以感染依赖的方式增加白细胞增殖。这一结果与现有模型一致，它们共同支持 E2F 信号对泰勒虫诱导的宿主细胞增殖的关键作用，以及一种或多种寄生虫蛋白对其的潜在直接操纵。
