DHHC7 Palmitoylates Glucose Transporter 4 (Glut4) and Regulates Glut4 Membrane Translocation
DHHC7 Palmitoylates Glucose Transporter 4 (Glut4) and Regulates Glut4 Membrane Translocation
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DOI：
10.1074/jbc.m116.747139
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发表时间：
2017-02-17
影响因子：
4.8
通讯作者：
Luscher, Bernhard
中科院分区：
文献类型：
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作者：
Du, Keyong;Murakami, Shoko;Luscher, Bernhard
葡萄糖转运蛋白4（Glut 4）的胰岛素依赖性转运在葡萄糖稳态的动态调节中起着关键作用。我们最近发现，这一过程严重依赖于Glut 4在Cys-223的棕榈酰化。为了进一步了解Glut 4棕榈酰化的调节，我们着手确定棕榈酰酰基转移酶（PAT）参与。在这里，我们报告说，在23种哺乳动物DHHC蛋白，DHHC 7是主要的Glut 4 PAT的基础上，证据表明，DHHC 7的异位表达增加Glut 4棕榈酰化，而DHHC 7敲低在3 T3-L1脂肪细胞和DHHC 7 KO在脂肪组织和肌肉减少Glut 4棕榈酰化。此外，DHHC 7的失活抑制了3 T3-L1脂肪细胞和原代脂肪细胞中胰岛素依赖性Glut 4膜转位。最后，DHHC 7 KO小鼠发展出高血糖症和葡萄糖耐受不良，从而证实DHHC 7代表Glut 4的主要PAT，并且该机制对于胰岛素调节的葡萄糖稳态是必需的。
Insulin-dependent translocation of glucose transporter 4 (Glut4) to the plasma membrane plays a key role in the dynamic regulation of glucose homeostasis. Werecently showed that this process is critically dependent on palmitoylation of Glut4 at Cys-223. To gain further insights into the regulation of Glut4 palmitoylation, we set out to identify the palmitoyl acyltransferase (PAT) involved. Here we report that among 23 mammalian DHHC proteins, DHHC7 is the major Glut4 PAT, based on evidence that ectopic expression of DHHC7 increased Glut4 palmitoylation, whereas DHHC7 knockdown in 3T3-L1 adipocytes andDHHC7KOin adipose tissue and muscle decreased Glut4 palmitoylation. Moreover, inactivation of DHHC7 suppressed insulin-dependent Glut4 membrane translocation in both 3T3-L1 adipocytes and primary adipocytes. Finally, DHHC7 KO mice developed hyperglycemia and glucose intolerance, thereby confirming that DHHC7 represents the principal PAT for Glut4 and that this mechanism is essential for insulin- regulated glucose homeostasis.