p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis.
p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis.
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我们发现p38丝裂原活化蛋白激酶（p38 MAPK）磷酸化Thr 48和Ser 61残基上的X-Box结合蛋白1（XBP 1 s）的剪接形式，并大大增强XBP 1 s的核迁移。Thr 48和Ser 61突变为丙氨酸显著降低了XBP 1的核转位和活性。我们还表明，p38 MAPK活性显着降低，在肥胖小鼠的肝脏和p38 MAPK的激活，组成型活性的MAP激酶激酶6（MKK 6 Glu）的表达大大增强了核转位的XBP 1，减少ER应激，并建立在严重肥胖和糖尿病小鼠的eukaryotic。因此，我们的研究结果定义了Thr 48和Ser 61磷酸化的XBP 1 s在维持肥胖症的葡萄糖稳态中的关键作用，并表明肥胖小鼠肝脏中的p38 MAPK激活可能为治疗2型糖尿病提供一种新的治疗方法。
Here we show that p38 mitogen activated protein kinase (p38 MAPK) phosphorylates spliced form of X-Box Binding Protein 1 (XBP1s) on Thr48 and Ser61 residues and greatly enhances nuclear migration of XBP1s. Mutation of Thr48 and Ser61 to alanine dramatically reduces nuclear translocation of XBP1s and activity. We also demonstrate that p38 MAPK activity is markedly reduced in the livers of obese mice and that activation of p38 MAPK by expression of constitutively active MAP Kinase Kinase 6 (MKK6Glu) greatly enhances nuclear translocation of XBP1s, reduces ER stress and establishes euglycemia in the severely obese and diabetic mice. Hence, our results define a crucial role for Thr48 and Ser61 phosphorylations of XBP1s in maintenance of glucose homeostasis in obesity and indicate that p38 MAPK activation in the livers of obese mice may provide a novel therapeutic approach for treatment of type 2 diabetes.