Toll pathway modulates TNF-induced JNK-dependent cell death in Drosophila.
Toll pathway modulates TNF-induced JNK-dependent cell death in Drosophila.
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Toll 通路调节果蝇中 TNF 诱导的 JNK 依赖性细胞死亡。
DOI：
10.1098/rsob.140171
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发表时间：
2015-07
期刊：
影响因子：
5.8
通讯作者：
Xue L
中科院分区：
文献类型：
--
作者：
Wu C;Chen C;Dai J;Zhang F;Chen Y;Li W;Pastor-Pareja JC;Xue L
控制细胞生与死的信号网络是现代生物学的核心。虽然c-Jun N-末端激酶（JNK）通路在调节细胞死亡中的作用已经得到了很好的确立，但调节JNK介导的细胞死亡的其他因素尚未完全阐明。为了鉴定JNK依赖性细胞死亡的新调节因子，我们在果蝇中进行了显性修饰筛选，发现Toll通路参与JNK介导的细胞死亡。Toll信号传导的丧失抑制异位和生理活化的JNK信号传导诱导的细胞死亡。我们的上位性分析表明，Toll途径充当JNK依赖性细胞死亡的下游调节剂。此外，JNK信号转导的获得导致Toll通路活化，这通过刺激的Drosomycin（Drs）转录和增加的Dorsal的胞质至核易位来揭示。此外，Toll受体的Spätzle（Spz）家族配体通过激活的JNK信号传导以非细胞自主的方式转录上调，为JNK诱导的Toll途径激活提供了分子机制。最后，Toll信号的获得加剧了JNK介导的细胞死亡，并促进了不依赖于半胱天冬酶的细胞死亡。因此，我们已经确定了另一个重要的功能，进化保守的Toll通路，除了其充分研究的作用，在胚胎背腹图案和先天免疫。
Signalling networks that control the life or death of a cell are of central interest in modern biology. While the defined roles of the c-Jun N-terminal kinase (JNK) pathway in regulating cell death have been well-established, additional factors that modulate JNK-mediated cell death have yet to be fully elucidated. To identify novel regulators of JNK-dependent cell death, we performed a dominant-modifier screen in Drosophila and found that the Toll pathway participates in JNK-mediated cell death. Loss of Toll signalling suppresses ectopically and physiologically activated JNK signalling-induced cell death. Our epistasis analysis suggests that the Toll pathway acts as a downstream modulator for JNK-dependent cell death. In addition, gain of JNK signalling results in Toll pathway activation, revealed by stimulated transcription of Drosomycin (Drs) and increased cytoplasm-to-nucleus translocation of Dorsal. Furthermore, the Spätzle (Spz) family ligands for the Toll receptor are transcriptionally upregulated by activated JNK signalling in a non-cell-autonomous manner, providing a molecular mechanism for JNK-induced Toll pathway activation. Finally, gain of Toll signalling exacerbates JNK-mediated cell death and promotes cell death independent of caspases. Thus, we have identified another important function for the evolutionarily conserved Toll pathway, in addition to its well-studied roles in embryonic dorso-ventral patterning and innate immunity.