XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands
XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands
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DOI：
10.1038/sj.emboj.7600903
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发表时间：
2005-12-21
期刊：
影响因子：
11.4
通讯作者：
Glimcher, LH
中科院分区：
文献类型：
--
作者：
Lee, AH;Chu, GC;Glimcher, LH
细胞的分泌功能依赖于内质网（ER）折叠和修饰新生多肽以及合成磷脂以用于随后通过ER-高尔基体网络运输分泌蛋白的能力。我们以前已经证明，转录因子XBP-1激活某些ER伴侣基因的表达，并启动ER生物合成。在这里，我们通过将XBP-1转基因选择性地靶向肝细胞（XBP-1（-/-）;Liv（XBP 1）），挽救了XBP-1缺陷胎儿的胚胎致死率。XBP-1（-/-）; Liv（XBP 1）小鼠的分泌器官（如胰腺外分泌和唾液腺）显示出异常，导致出生后早期胰腺消化酶产生受损导致死亡。胰腺和唾液腺腺泡细胞ER发育不良，伴ER伴侣基因表达减少。胰腺腺泡细胞在胚胎发育过程中出现明显的凋亡。因此，XBP-1的缺乏导致ER上的货物负载与其处理能力之间的不平衡，导致ER应激介导的促凋亡途径的激活。这些数据使我们提出，XBP-1是必要的和充分的外分泌细胞中的分泌机制的完整的生物合成。
The secretory function of cells relies on the capacity of the endoplasmic reticulum (ER) to fold and modify nascent polypeptides and to synthesize phospholipids for the subsequent trafficking of secretory proteins through the ER-Golgi network. We have previously demonstrated that the transcription factor XBP-1 activates the expression of certain ER chaperone genes and initiates ER biogenesis. Here, we have rescued the embryonic lethality of XBP-1 deficient fetuses by targeting an XBP-1 transgene selectively to hepatocytes (XBP-1(-/-);Liv(XBP1)). XBP-1(-/-);Liv(XBP1) mice displayed abnormalities exclusively in secretory organs such as exocrine pancreas and salivary gland that led to early postnatal lethality from impaired production of pancreatic digestive enzymes. The ER was poorly developed in pancreatic and salivary gland acinar cells, accompanied by decreased expression of ER chaperone genes. Marked apoptosis of pancreatic acinar cells was observed during embryogenesis. Thus, the absence of XBP-1 results in an imbalance between the cargo load on the ER and its capacity to handle it, leading to the activation of ER stress-mediated proapoptotic pathways. These data lead us to propose that XBP-1 is both necessary and sufficient for the full biogenesis of the secretory machinery in exocrine cells.