Pelle Modulates dFoxO-Mediated Cell Death in Drosophila.
Pelle Modulates dFoxO-Mediated Cell Death in Drosophila.
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Pelle 调节 dFoxO 介导的果蝇细胞死亡。
DOI：
10.1371/journal.pgen.1005589
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Xue L
中科院分区：
文献类型：
--
作者：
Wu C;Chen Y;Wang F;Chen C;Zhang S;Li C;Li W;Wu S;Xue L
白介素 1 受体相关激酶 (IRAK) 是调节哺乳动物免疫和炎症反应的 IL-1R/TLR 信号通路的重要介质。最近的研究还表明，IRAK 在肿瘤发展中发挥着关键作用，但其潜在机制仍不清楚。 Pelle 是与保守的 Toll 通路相关的唯一果蝇 IRAK 同源物，该通路调节背侧/腹侧模式、先天免疫反应、肌肉发育和轴突引导。在这里，我们报告了 pll 在调节细胞凋亡中的一种新功能，该功能独立于 Toll 途径。我们发现 pll 的丢失会导致翼组织尺寸减小，这是由细胞数量减少引起的，而不是细胞尺寸减少。 pll 的耗尽会上调促凋亡基因的转录，并触发 caspase 激活和细胞死亡。转录因子 dFoxO 是 pll 丢失诱导的细胞死亡所必需的。此外，pll的丢失会激活dFoxO，促进其从细胞质易位到细胞核，并上调其靶基因Thor/4E-BP的转录。最后，Pll 与 dFoxO 发生物理相互作用并直接磷酸化 dFoxO。这项研究不仅确定了 pll 在细胞死亡中以前未知的生理功能，而且揭示了 IRAK 在肿瘤发生过程中细胞存活/死亡的机制。在本研究中，我们报告了 Pll 在调节细胞凋亡中的 Toll 途径独立功能。我们的主要发现包括：1）pll 的丢失会产生不依赖于 Toll 通路的翼表型，这是由细胞数量减少而非细胞大小减少引起的； 2) pll的消耗上调促凋亡基因hid、reaper和grim的转录，并触发caspase介导的细胞死亡，而细胞增殖不受影响； 3）pll通过转录因子dFoxO调节caspase激活和细胞死亡； 4) pll的丢失促进dFoxO从细胞质易位到细胞核，并激活dFoxO靶基因Thor/4E-BP的转录； 5) Pll与dFoxO发生物理相互作用并直接磷酸化dFoxO。因此，这项工作描述了 pll 先前未知的独立于 Toll 途径的生理功能。
Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals. Recent studies also suggest a critical role of IRAKs in tumor development, though the underlying mechanism remains elusive. Pelle is the sole Drosophila IRAK homolog implicated in the conserved Toll pathway that regulates Dorsal/Ventral patterning, innate immune response, muscle development and axon guidance. Here we report a novel function of pll in modulating apoptotic cell death, which is independent of the Toll pathway. We found that loss of pll results in reduced size in wing tissue, which is caused by a reduction in cell number but not cell size. Depletion of pll up-regulates the transcription of pro-apoptotic genes, and triggers caspase activation and cell death. The transcription factor dFoxO is required for loss-of-pll induced cell death. Furthermore, loss of pll activates dFoxO, promotes its translocation from cytoplasm to nucleus, and up-regulates the transcription of its target gene Thor/4E-BP. Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly. This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis. In the present study we report a Toll pathway independent function of Pll in modulating apoptotic cell death. Our major findings include: 1) loss of pll generates Toll pathway-independent wing phenotypes, which are caused by a reduction in cell number but not cell size; 2) depletion of pll up-regulates the transcription of pro-apoptotic genes hid, reaper and grim, and triggers caspase-mediated cell death, whereas cell proliferation remains unaffected; 3) pll modulates caspase activation and cell death through the transcription factor dFoxO; 4) loss of pll promotes dFoxO translocation from cytoplasm to nucleus, and activates the transcription of dFoxO target gene Thor/4E-BP; 5) Pll physically interacts with dFoxO and phosphorylates dFoxO directly. Thus, this work characterizes a previously unknown physiological function of pll that is independent of the Toll pathway.