PKA phosphorylation couples hepatic inositol-requiring enzyme 1α to glucagon signaling in glucose metabolism
PKA phosphorylation couples hepatic inositol-requiring enzyme 1α to glucagon signaling in glucose metabolism
复制标题
DOI：
10.1073/pnas.1107394108
复制
发表时间：
2011-09-20
影响因子：
11.1
通讯作者：
Liu, Yong
中科院分区：
文献类型：
--
作者：
Mao, Ting;Shao, Mengle;Liu, Yong
内质网(ER)驻留的蛋白激酶/内切核酸酶-肌醇需要酶1(IRE1)在内质网(ER)管腔内的蛋白质折叠超载时通过反式自磷酸化被激活，并通过触发未折叠蛋白质反应的关键分支来维持内质网的动态平衡。在这里，我们展示了哺乳动物肝细胞中的IRE1α也被一种不同于自身的激酶磷酸化，以响应代谢刺激。胰升糖素刺激的蛋白激酶PKA，进而使IRE1α在Ser(724)处磷酸化，Ser(724)是一个高度保守的位置。阻断Ser(724)的磷酸化削弱了IRE1α通过胰高血糖素信号上调糖异生基因表达的能力。此外，肥胖小鼠肝脏IRE1α在Ser(724)处被PKA高度磷酸化，沉默肝脏IRE1α可显著降低高血糖和糖耐量。因此，这些结果表明，IRE1α整合了来自肝脏内质网和细胞质的信号，并与葡萄糖代谢调节中的胰高血糖素信号偶联。
The endoplasmic reticulum (ER)-resident protein kinase/endoribo-nuclease inositol-requiring enzyme 1 (IRE1) is activated through transautophosphorylation in response to protein folding overload in the ER lumen and maintains ER homeostasis by triggering a key branch of the unfolded protein response. Here we show that mammalian IRE1 alpha in liver cells is also phosphorylated by a kinase other than itself in response to metabolic stimuli. Glucagon-stimulated protein kinase PKA, which in turn phosphorylated IRE1 alpha at Ser(724), a highly conserved site within the kinase activation domain. Blocking Ser(724) phosphorylation impaired the ability of IRE1 alpha to augment the up-regulation by glucagon signaling of the expression of gluconeogenic genes. Moreover, hepatic IRE1 alpha was highly phosphorylated at Ser(724) by PKA in mice with obesity, and silencing hepatic IRE1 alpha markedly reduced hyperglycemia and glucose intolerance. Hence, these results suggest that IRE1 alpha integrates signals from both the ER lumen and the cytoplasm in the liver and is coupled to the glucagon signaling in the regulation of glucose metabolism.