Waldhart Althea N, Dykstra Holly, Peck Anderson S, Boguslawski Elissa A, Madaj Zachary B, Wen Jennifer, Veldkamp Kelsey, Hollowell Matthew, Zheng Bin, Cantley Lewis C, McGraw Timothy E, Wu Ning
Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA.
Cell Rep. 2017 Jun 6;19(10):2005-2013. doi: 10.1016/j.celrep.2017.05.041.
Growth factors, such as insulin, can induce both acute and long-term glucose uptake into cells. Apart from the rapid, insulin-induced fusion of glucose transporter (GLUT)4 storage vesicles with the cell surface that occurs in muscle and adipose tissues, the mechanism behind acute induction has been unclear in other systems. Thioredoxin interacting protein (TXNIP) has been shown to be a negative regulator of cellular glucose uptake. TXNIP is transcriptionally induced by glucose and reduces glucose influx by promoting GLUT1 endocytosis. Here, we report that TXNIP is a direct substrate of protein kinase B (AKT) and is responsible for mediating AKT-dependent acute glucose influx after growth factor stimulation. Furthermore, TXNIP functions as an adaptor for the basal endocytosis of GLUT4 in vivo, its absence allows excess glucose uptake in muscle and adipose tissues, causing hypoglycemia during fasting. Altogether, TXNIP serves as a key node of signal regulation and response for modulating glucose influx through GLUT1 and GLUT4.
生长因子，如胰岛素，可诱导细胞对葡萄糖进行急性和长期摄取。除了在肌肉和脂肪组织中发生的胰岛素诱导的葡萄糖转运蛋白4（GLUT4）储存囊泡与细胞表面的快速融合外，其他系统中急性诱导背后的机制尚不清楚。硫氧还蛋白相互作用蛋白（TXNIP）已被证明是细胞葡萄糖摄取的负调节因子。TXNIP由葡萄糖转录诱导，并通过促进GLUT1内吞作用减少葡萄糖内流。在这里，我们报告TXNIP是蛋白激酶B（AKT）的直接底物，并负责介导生长因子刺激后AKT依赖的急性葡萄糖内流。此外，TXNIP在体内作为GLUT4基础内吞作用的衔接子，其缺失会导致肌肉和脂肪组织中葡萄糖摄取过多，在禁食期间导致低血糖。总之，TXNIP作为信号调节和反应的关键节点，通过GLUT1和GLUT4调节葡萄糖内流。
