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首页> 外文期刊>PLoS Genetics >Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis
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Control of RUNX-induced repression of Notch signaling by MLF and its partner DnaJ-1 during Drosophila hematopoiesis

机译：果蝇造血过程中，MLF及其伴侣DnaJ-1对RUNX诱导的Notch信号的抑制的控制

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A tight regulation of transcription factor activity is critical for proper development. For instance, modifications of RUNX transcription factors dosage are associated with several diseases, including hematopoietic malignancies. In Drosophila, Myeloid Leukemia Factor (MLF) has been shown to control blood cell development by stabilizing the RUNX transcription factor Lozenge (Lz). However, the mechanism of action of this conserved family of proteins involved in leukemia remains largely unknown. Here we further characterized MLF’s mode of action in Drosophila blood cells using proteomic, transcriptomic and genetic approaches. Our results show that MLF and the Hsp40 co-chaperone family member DnaJ-1 interact through conserved domains and we demonstrate that both proteins bind and stabilize Lz in cell culture, suggesting that MLF and DnaJ-1 form a chaperone complex that directly regulates Lz activity. Importantly, dnaj-1 loss causes an increase in Lz+ blood cell number and size similarly as in mlf mutant larvae. Moreover we find that dnaj-1 genetically interacts with mlf to control Lz level and Lz+ blood cell development in vivo. In addition, we show that mlf and dnaj-1 loss alters Lz+ cell differentiation and that the increase in Lz+ blood cell number and size observed in these mutants is caused by an overactivation of the Notch signaling pathway. Finally, using different conditions to manipulate Lz activity, we show that high levels of Lz are required to repress Notch transcription and signaling. All together, our data indicate that the MLF/DnaJ-1-dependent increase in Lz level allows the repression of Notch expression and signaling to prevent aberrant blood cell development. Thus our findings establish a functional link between MLF and the co-chaperone DnaJ-1 to control RUNX transcription factor activity and Notch signaling during blood cell development in vivo.
机译：转录因子活性的严格调节对于正确发育至关重要。例如，RUNX转录因子剂量的改变与几种疾病有关，包括造血系统恶性肿瘤。在果蝇中，髓样白血病因子（MLF）已显示可通过稳定RUNX转录因子锭剂（Lz）来控制血细胞发育。但是，这种涉及白血病的保守蛋白家族的作用机理仍然是未知的。在这里，我们使用蛋白质组学，转录组学和遗传学方法进一步表征了果蝇血细胞中MLF的作用方式。我们的结果表明，MLF和Hsp40伴侣分子DnaJ-1通过保守结构域相互作用，并且我们证明了两种蛋白都可以结合并稳定细胞培养物中的Lz，表明MLF和DnaJ-1形成了直接调节Lz活性的伴侣复合物。 。重要的是，dnaj-1的丢失会导致Lz +血细胞数量和大小的增加，类似于mlf突变幼虫。此外，我们发现dnaj-1在体内与mlf发生基因相互作用，以控制Lz水平和Lz +血细胞发育。此外，我们表明mlf和dnaj-1丢失会改变Lz +细胞的分化，并且在这些突变体中观察到的Lz +血细胞数量和大小的增加是由Notch信号通路的过度激活引起的。最后，使用不同的条件来操纵Lz活性，我们表明需要高水平的Lz来抑制Notch转录和信号传导。总之，我们的数据表明Lz水平的MLF / DnaJ-1依赖性增加可抑制Notch表达和信号转导，以防止异常血细胞发育。因此，我们的发现建立了MLF和伴侣分子DnaJ-1之间的功能性联系，以在体内血细胞发育过程中控制RUNX转录因子的活性和Notch信号传导。

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