IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA
IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA
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作者：
Calfon, M;Zeng, HQ;Ron, D
由应激引起的未折叠蛋白反应（UPR）使内质网（ER）的折叠能力与细胞器中客户蛋白的负载相匹配（1，2）。在酵母中，激活的Ire 1对HAC 1 mRNA的加工导致转录因子Hac 1的合成和UPR 3的激活。后生动物对激活的IRE 1的反应还不太清楚。在这里，我们证明，无论是ire-1或转录因子编码xbp-1基因的突变废除了秀丽隐杆线虫的UPR。哺乳动物XBP-1对免疫球蛋白分泌和浆细胞发育至关重要（4），在特化分泌细胞中发现高水平的XBP-1信使RNA（5）。UPR的激活导致IRE 1依赖性剪接XBP-1 mRNA中的一个小内含子。线虫和老鼠在UPR期间，由加工的鼠XBP-1 mRNA编码的蛋白质积累，而由未加工的mRNA编码的蛋白质没有积累。纯化的小鼠IRE 1在体外准确地切割XBP-1 mRNA，表明XBP-1 mRNA是IRE 1内切核酸酶活性的直接靶点。我们的研究结果表明，生理ER负荷调节高等真核生物的发育决策。
The unfolded protein response (UPR), caused by stress, matches the folding capacity of endoplasmic reticulum (ER) to the load of client proteins in the organelle(1,2). In yeast, processing of HAC1 mRNA by activated Ire1 leads to synthesis of the transcription factor Hac1 and activation of the UPR3. The responses to activated IRE1 in metazoans are less well understood. Here we demonstrate that mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans. Mammalian XBP-1 is essential for immunoglobulin secretion and development of plasma cells(4), and high levels of XBP-1 messenger RNA are found in specialized secretory cells(5). Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA both in C. elegans and mice. The protein encoded by the processed murine XBP-1 mRNA accumulated during the UPR, whereas the protein encoded by unprocessed mRNA did not. Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity. Our findings suggest that physiological ER load regulates a developmental decision in higher eukaryotes.