Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein
Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein
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DOI：
10.1016/j.cmet.2005.09.005
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发表时间：
2005-10-01
期刊：
影响因子：
29
通讯作者：
McGraw, TE
中科院分区：
文献类型：
--
作者：
Eguez, L;Lee, A;McGraw, TE
胰岛素通过调节GLUT4在细胞内部和表面的转运来控制葡萄糖进入肌肉和脂肪的流量。在这里，我们证明了AS160Rab GTPase激活蛋白(GAP)是基础GLUT4胞吐的负调节因子。AS160基因敲除导致GLUT4从细胞内室到质膜的部分重新分配，伴随而来的是基础葡萄糖摄取量的增加，以及基础GLUT4胞吐能力的3倍增加。野生型AS160的重新表达使击倒的脂肪细胞恢复了正常的GLUT4行为，而GAP结构域突变体的重新表达并没有恢复表型，这提供了第一个直接证据，表明AS160的GAP活性是基础GLUT4保持所必需的。AS160是第一个被鉴定为基础GLUT4保留所特别需要的蛋白质。我们的研究发现，AS160基因敲除仅部分释放基础GLUT4滞留，这为胰岛素通过AS160依赖和非依赖机制向GLUT4胞吐提供了证据。
Insulin controls glucose flux into muscle and fat by regulating the trafficking of GLUT4 between the interior and surface of cells. Here, we show that the AS160 Rab GTPase activating protein (GAP) is a negative regulator of basal GLUT4 exocytosis. AS160 knockdown resulted in a partial redistribution of GLUT4 from intracellular compartments to the plasma membrane, a concomitant increase in basal glucose uptake, and a 3-fold increase in basal GLUT4 exocytosis. Reexpression of wild-type AS160 restored normal GLUT4 behavior to the knockdown adipocytes, whereas reexpression of a GAP domain mutant did not revert the phenotype, providing the first direct evidence that AS160 GAP activity is required for basal GLUT4 retention. AS160 is the first protein identified that is specially required for basal GLUT4 retention. Our findings that AS160 knockdown only partially releases basal GLUT4 retention provides evidence that insulin signals to GLUT4 exocytosis by both AS160-dependent and -independent mechanisms.