Deficient Notch signaling associated with neurogenic pecanex is compensated for by the unfolded protein response in Drosophila
Deficient Notch signaling associated with neurogenic pecanex is compensated for by the unfolded protein response in Drosophila
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DOI：
10.1242/dev.073858
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发表时间：
2012-02
期刊：
影响因子：
4.6
通讯作者：
Tomoko Yamakawa;Kenta Yamada;Takeshi Sasamura;Naotaka Nakazawa;M. Kanai;E. Suzuki;M. Fortini;K. Matsuno
中科院分区：
文献类型：
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作者：
Tomoko Yamakawa;Kenta Yamada;Takeshi Sasamura;Naotaka Nakazawa;M. Kanai;E. Suzuki;M. Fortini;K. Matsuno
Notch（N）信号机制在进化上是保守的，并通过局部细胞间通讯调节广谱的细胞特异性事件。pecanex（pcx）编码一种功能未知的多通道跨膜蛋白，广泛存在于果蝇和人类中。在果蝇中pcx的合子和母体缺失导致神经原性表型（胚胎神经系统的增生），这表明pcx可能参与N信号传导。在这里，我们确定Pcx是N-信号通路的一个组成部分。Pcx需要上游的膜栓和核形式的活化N，可能在N信号接收细胞，这表明，pcx是需要之前或期间的N的活化。pcx过表达表明Pcx存在于内质网（ER）中。pcx功能的破坏导致扩大的ER，这是不可归因于减少N信号传导活性。此外，过度诱导的未折叠蛋白反应（UPR）的表达激活Xbp 1或显性负性热休克蛋白同源3抑制的神经原性表型和ER扩大所造成的情况下的pcx。一个类似的抑制这些表型诱导过表达的O-岩藻糖基转移酶1，N-特异性伴侣。将这些结果结合在一起，我们推测，在缺乏pcx功能的胚胎中N信号的减少可能是由于ER功能缺陷，这是通过上调UPR和可能通过增强N折叠来补偿的。我们的研究结果表明，ER在N信号中起着以前未被认识到的作用，这种ER功能依赖于pcx活性。
The Notch (N) signaling machinery is evolutionarily conserved and regulates a broad spectrum of cell-specification events, through local cell-cell communication. pecanex (pcx) encodes a multi-pass transmembrane protein of unknown function, widely found from Drosophila to humans. The zygotic and maternal loss of pcx in Drosophila causes a neurogenic phenotype (hyperplasia of the embryonic nervous system), suggesting that pcx might be involved in N signaling. Here, we established that Pcx is a component of the N-signaling pathway. Pcx was required upstream of the membrane-tethered and the nuclear forms of activated N, probably in N signal-receiving cells, suggesting that pcx is required prior to or during the activation of N. pcx overexpression revealed that Pcx resides in the endoplasmic reticulum (ER). Disruption of pcx function resulted in enlargement of the ER that was not attributable to the reduced N signaling activity. In addition, hyper-induction of the unfolded protein response (UPR) by the expression of activated Xbp1 or dominant-negative Heat shock protein cognate 3 suppressed the neurogenic phenotype and ER enlargement caused by the absence of pcx. A similar suppression of these phenotypes was induced by overexpression of O-fucosyltransferase 1, an N-specific chaperone. Taking these results together, we speculate that the reduction in N signaling in embryos lacking pcx function might be attributable to defective ER functions, which are compensated for by upregulation of the UPR and possibly by enhancement of N folding. Our results indicate that the ER plays a previously unrecognized role in N signaling and that this ER function depends on pcx activity.