Vertebrate Unfolded Protein Response: Mammalian Signaling Pathways Are Conserved in Medaka Fish
Vertebrate Unfolded Protein Response: Mammalian Signaling Pathways Are Conserved in Medaka Fish
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DOI：
10.1247/csf.11036
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发表时间：
2011-01-01
影响因子：
1.5
通讯作者：
Mori, Kazutoshi
中科院分区：
文献类型：
--
作者：
Ishikawa, Tokiro;Taniguchi, Yoshihito;Mori, Kazutoshi
未折叠蛋白在内质网（ER）中的积累激活了未折叠蛋白反应（UPR）。内质网应激信号由内质网中的跨膜蛋白感知和传递。这些传感器的数量随着进化而增加，酵母中有一个，蠕虫和苍蝇中有三个，哺乳动物中有五个。在这里，我们检查了medaka鱼，Oryzias latipes，作为一种脊椎动物模式生物，发现medaka基因组编码5个UPR传感器。对medaka胚胎细胞系的分析表明，哺乳动物UPR信号机制是非常保守的。因此，编码IRE1通路下游转录因子XBP1的XBP1 mRNA在内质网应激下被剪接，从而产生活性形式的XBP1。在内质网应激下，翻译通常会减弱，这反过来诱导了PERK通路下游转录因子ATF4的翻译。ATF6作为跨膜蛋白组成性合成，并通过内质网应激诱导的蛋白水解激活。活性ATF6a、ATF6 β和XBP1过表达的结果强烈表明，ATF6a在上调主要ER伴侣BiP中起主要作用，这与非脊椎动物的情况相反，在非脊椎动物中，IRE1途径对诱导BiP至关重要。在BiP启动子控制下，利用携带增强型绿色荧光蛋白基因的转基因medaka，观察胚胎发育过程中发生的生理内质网应激。因此，利用medaka对脊椎动物普遍定期审议进行分析将有助于更全面地了解普遍定期审议的生物学和生理学。
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). The ER stress signal is sensed and transmitted by a transmembrane protein(s) in the ER. The number of these transducers has increased with evolution, one in yeast, three in worm and fly, and five in mammals. Here, we examined medaka fish, Oryzias latipes, as a vertebrate model organism, and found that the medaka genome encodes five UPR transducers. Analysis of a medaka embryonic cell line revealed that the mammalian UPR signaling mechanisms are very well conserved. Thus, XBP1 mRNA, which encodes the transcription factor XBP1 downstream of the IRE1 pathway, was spliced in response to ER stress, resulting in production of the active form of XBP1. Translation was generally attenuated in response to ER stress, which paradoxically induced the translation of ATF4, the transcription factor downstream of the PERK pathway. ATF6 was constitutively synthesized as a transmembrane protein and activated by ER stress-induced proteolysis. Results obtained with the overexpression of active ATF6a, ATF6 beta, and XBP1 strongly suggested that ATF6a plays a major role in upregulating the major ER chaperone BiP, contrary to the case in non-vertebrates, in which the IRE1 pathway is essential to the induction of BiP. Physiological ER stress occurring during embryonic development was visualized using transgenic medaka carrying the enhanced green fluorescent protein gene under the control of the BiP promoter. Thus, analysis of the vertebrate UPR using medaka will help provide a more comprehensive understanding of the biology and physiology of the UPR.