Analysis of an intracellular signaling from the endoplasmic reticulum to the nucleus

内质网是新合成的分泌蛋白和跨膜蛋白折叠和质量控制的场所。当内质网应激条件下未折叠蛋白在内质网中积累时，未折叠蛋白反应（UPR），一种转录诱导程序，结合从内质网到细胞核的细胞内信号，被激活以维持内质网的稳态。我们已经证明ATF6和IRE1-XBP1通路在哺乳动物UPR中发挥重要作用。ATF6是一种由蛋白水解激活的内质网膜结合转录因子。另一方面，XBP1是一个转录因子，其mRNA被IRE1剪接。基于ATF6和XBP1激活时间过程的差异和DNA结合特异性的差异，我们提出了哺乳动物UPR的时间依赖相移，即从内源性ER伴侣（仅重折叠）的第一阶段，到由ATF6途径诱导的ER伴侣（仅重折叠）的第二阶段，到由IRE1-XBP1途径诱导的ER伴侣和ERAD成分（重折叠加降解）的第三阶段。取决于内质网中未折叠蛋白质的质量或数量。内质网在专门合成和分泌抗体的浆细胞等专业分泌细胞中得到扩展。我们发现过表达XBP1刺激内质膜主要成分磷脂酰胆碱和磷脂酰乙醇胺的合成，表明XBP1是连接蛋白质质量控制与细胞器生物发生的关键因素。

The endoplamic reticulum (ER) is the place for folding and quality control of newly synthesized secretory and transmembrane proteins. When unfolded proteins are accumulated in the ER under ER stress conditions, the unfolded protein response (UPR), a transcriptional induction program coupled with intracellular signaling from the ER to the nucleus, is activated to maintain the homeostasis of the ER. We have shown that the ATF6 and IRE1-XBP1 pathways play important roles in mammalian UPR. ATF6 is an ER membrane-bound transcription factor activated by proteolysis. On the other hand, XBP1 is a transcription factor whose mRNA is spliced by IRE1. Base on the difference in activation time course and the difference in DNA binding specificity between ATF6 and XBP1, we proposed a time-dependent phase shift in the mammalian UPR, that is shifted from the first phase dealt with endogenous ER chaperones (refolding only), to the second phase dealt with ER chaperones induced by the ATF6 pathway(refolding only), and to the third phase dealt with ER chaperones and ERAD components induced by the IRE1-XBP1 pathway (refolding plus degradation), depending on quality or quantity of unfolded proteins accumulated in the ER.The ER is expanded in professional secretory cells such as plasma cells which is specialized for synthesis and secretion of antibody. We found that overexpression of XBP1 stimulates synthesis of phosphatidylcholine and phosphatidylethanolamine, major components of the ER membrane, and indicated that XBP1 is a key factor connecting quality control of proteins with organelle biogenesis.