SUMOylation of Pancreatic Glucokinase Regulates Its Cellular Stability and Activity
SUMOylation of Pancreatic Glucokinase Regulates Its Cellular Stability and Activity
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DOI：
10.1074/jbc.m112.393769
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发表时间：
2013-02-22
影响因子：
4.8
通讯作者：
Njolstad, Pal R.
中科院分区：
文献类型：
--
作者：
Aukrust, Ingvild;Bjorkhaug, Lise;Njolstad, Pal R.
葡萄糖激酶是在肝细胞和胰腺β细胞中表达的主要己糖激酶，在调节葡萄糖刺激的胰岛素分泌中具有关键作用，通过引起单基因糖尿病和先天性高胰岛素血症性低血糖的葡萄糖激酶基因突变来说明。一个复杂的组织特异性机制网络调节这种酶，葡萄糖激酶生物学中的一个主要未回答的问题是翻译后修饰如何控制酶的功能。在这里，我们表明，胰腺亚型的人葡萄糖激酶是SUMO化的体外，使用重组酶，在胰岛素分泌模型细胞。胰腺同种型特有的三个N-末端赖氨酸（Lys-12/Lys-13和/或Lys-15）可能代表一个SUMO化位点，另外一个位点（Lys-346）是胰腺和肝脏同种型共有的。SUMO-1和E2过表达优先稳定MIN 6 β细胞中的野生型人胰腺酶，SUMO化增加了体外重组人葡萄糖激酶和靶细胞中葡萄糖激酶的催化活性。小泛素样修饰物缀合代表了酶的翻译后修饰的新形式，并且它可能在胰腺β细胞中具有重要的调节功能。
Glucokinase is the predominant hexokinase expressed in hepatocytes and pancreatic beta-cells, with a pivotal role in regulating glucose-stimulated insulin secretion, illustrated by glucokinase gene mutations causing monogenic diabetes and congenital hyperinsulinemic hypoglycemia. A complex tissue-specific network of mechanisms regulates this enzyme, and a major unanswered question in glucokinase biology is how post-translational modifications control the function of the enzyme. Here, we show that the pancreatic isoform of human glucokinase is SUMOylated in vitro, using recombinant enzymes, and in insulin-secreting model cells. Three N-terminal lysines unique for the pancreatic isoform (Lys-12/Lys-13 and/or Lys-15) may represent one SUMOylation site, with an additional site (Lys-346) common for the pancreatic and the liver isoform. SUMO-1 and E2 overexpression stabilized preferentially the wild-type human pancreatic enzyme in MIN6 beta-cells, and SUMOylation increased the catalytic activity of recombinant human glucokinase in vitro and also of glucokinase in target cells. Small ubiquitin-like modifier conjugation represents a novel form of post-translational modification of the enzyme, and it may have an important regulatory function in pancreatic beta-cells.