Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
Mol Biol Cell. 2013 May;24(9):1387-95. doi: 10.1091/mbc.E12-11-0830. Epub 2013 Feb 27.
ATF6α and ATF6β are membrane-bound transcription factors activated by regulated intramembrane proteolysis in response to endoplasmic reticulum (ER) stress to induce various ER quality control proteins. ATF6α- and ATF6β single-knockout mice develop normally, but ATF6α/β double knockout causes embryonic lethality, the reason for which is unknown. Here we show in medaka fish that ATF6α is primarily responsible for transcriptional induction of the major ER chaperone BiP and that ATF6α/β double knockout, but not ATF6α- or ATF6β single knockout, causes embryonic lethality, as in mice. Analyses of ER stress reporters reveal that ER stress occurs physiologically during medaka early embryonic development, particularly in the brain, otic vesicle, and notochord, resulting in ATF6α- and ATF6β-mediated induction of BiP, and that knockdown of the α1 chain of type VIII collagen reduces such ER stress. The absence of transcriptional induction of several ER chaperones in ATF6α/β double knockout causes more profound ER stress and impaired notochord development, which is partially rescued by overexpression of BiP. Thus ATF6α/β-mediated adjustment of chaperone levels to increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis before formation of the vertebra.
ATF6α 和 ATF6β 是膜结合转录因子，通过内质网（ER）应激时的调控性跨膜蛋白水解激活，以诱导各种 ER 质量控制蛋白。ATF6α 和 ATF6β 单敲除小鼠正常发育，但 ATF6α/β 双敲除导致胚胎致死，原因尚不清楚。在这里，我们在斑马鱼中表明，ATF6α 主要负责主要 ER 伴侣蛋白 BiP 的转录诱导，并且 ATF6α/β 双敲除，而不是 ATF6α 或 ATF6β 单敲除，导致胚胎致死，如在小鼠中一样。对 ER 应激报告基因的分析表明，ER 应激在斑马鱼早期胚胎发育过程中发生生理上，特别是在大脑、耳囊和脊索中，导致 ATF6α 和 ATF6β 介导的 BiP 诱导，并且 VIII 型胶原的 α1 链的敲低减少了这种 ER 应激。在 ATF6α/β 双敲除中，几种 ER 伴侣蛋白的转录诱导缺失导致更严重的 ER 应激和脊索发育受损，而过表达 BiP 可部分挽救。因此，ATF6α/β 介导的对 ER 中增加的需求的伴侣蛋白水平的调节对于脊索的发育是必不可少的，脊索合成和分泌大量细胞外基质蛋白，在形成脊椎之前作为身体轴。
