ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish.
ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish.
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DOI：
10.1091/mbc.e12-11-0830
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发表时间：
2013-05
影响因子：
3.3
通讯作者：
Mori K
中科院分区：
文献类型：
--
作者：
Ishikawa T;Okada T;Ishikawa-Fujiwara T;Todo T;Kamei Y;Shigenobu S;Tanaka M;Saito TL;Yoshimura J;Morishita S;Toyoda A;Sakaki Y;Taniguchi Y;Takeda S;Mori K
内质网 (ER) 膜结合转录因子 ATF6α 和 ATF6β 介导分子伴侣水平的调整，以满足 ER 需求的增加，这对于脊索的发育至关重要；后者在椎骨形成之前合成并分泌大量细胞外基质蛋白作为身体轴。 ATF6α 和 ATF6β 是膜结合转录因子，通过响应内质网 (ER) 应激而调节的膜内蛋白水解作用激活，诱导各种 ER 质量控制蛋白。 ATF6α-和ATF6β单敲除小鼠发育正常，但ATF6α/β双敲除会导致胚胎致死，其原因尚不清楚。在这里，我们在青鳉鱼中发现，ATF6α 主要负责主要 ER 伴侣 BiP 的转录诱导，并且 ATF6α/β 双敲除（而不是 ATF6α- 或 ATF6β 单敲除）会导致胚胎致死，如在小鼠中。对 ER 应激报告基因的分析表明，在青鳉早期胚胎发育过程中，ER 应激在生理上发生，特别是在大脑、耳泡和脊索中，导致 ATF6α 和 ATF6β 介导的 BiP 诱导，而 VIII 型胶原蛋白 α1 链的敲除可减少此类 ER 应激。 ATF6α/β 双敲除中几个 ER 伴侣的转录诱导缺失会导致更严重的 ER 应激和脊索发育受损，而 BiP 的过度表达可以部分挽救这一情况。因此，ATF6α/β介导的伴侣水平调整以适应内质网需求的增加对于脊索的发育至关重要，脊索合成并分泌大量细胞外基质蛋白，在椎骨形成之前充当身体轴。
The endoplasmic reticulum (ER) membrane-bound transcription factors ATF6α and ATF6β mediate adjustment of chaperone levels to increased demands in the ER, which is essential for development of the notochord; the latter synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis before formation of the vertebra. 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.