Caenorhabditis elegans ortholog of a diabetes susceptibility locus:: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer
Caenorhabditis elegans ortholog of a diabetes susceptibility locus:: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer
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DOI：
10.1073/pnas.0601931103
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发表时间：
2006-08-08
影响因子：
11.1
通讯作者：
Hanover, John A.
中科院分区：
文献类型：
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作者：
Forsythe, Michele E.;Love, Dona C.;Hanover, John A.
O-连接N-乙酰氨基葡萄糖(O-GlcNAc)的添加和移除作用于核孔蛋白、转录因子和激酶的动态循环，调节细胞信号级联反应。两种高度保守的酶(O-GlcNAc转移酶和O-GlcNAcase)催化这一营养驱动的“氨基己糖信号通路”的最后步骤。人类O-GlcNAcase基因的单核苷酸多态性与2型糖尿病有关。在这里，我们发现秀丽线虫OGA-1编码一个活性的O-GlcNAcase。我们还描述了一种敲除等位基因OGA-1(Ok1207)，它是活的和可育的，但在核孔和其他细胞蛋白上积累OGlcNAc。用OGA-1(Ok1207)或O-GlcNAc转移酶缺失的OGT-1(Ok430)干扰O-GlcNAc循环可改变丝氨酸和苏氨酸磷酸蛋白谱，并增加糖原合成酶3β(GSK-3β)水平。OGA-1(OK1207)和OGT-1(OK430)菌株均显示糖原和海藻糖储存增加，脂肪储存减少。这些显著的代谢变化促使我们研究控制C elegans O-GlcNAc循环突变体中营养储存、寿命和Dauer形成的胰岛素样信号通路。事实上，我们发现，在OGT-1(Ok430)缺失的条件下，OGA-1(Ok1207)基因敲除增强了温度敏感型胰岛素样受体(daf-2)突变体诱导的达尔形成。我们的发现表明，O-GlcNAc的酶循环“微调”胰岛素样信号对营养流量的反应。线虫O-GlcNAcase(OGA-1)基因的敲除模拟了许多与人类胰岛素抵抗相关的代谢和信号变化，并提供了一种遗传上可接受的非胰岛素依赖型糖尿病模型。
A dynamic cycle of O-linked N-acetylglucosamine (O-GlcNAc) addition and removal acts on nuclear pore proteins, transcription factors, and kinases to modulate cellular signaling cascades. Two highly conserved enzymes (O-GlcNAc transferase and O-GlcNAcase) catalyze the final steps in this nutrient-driven "hexosamine-signaling pathway." A single nucleotide polymorphism in the human O-GlcNAcase gene is linked to type 2 diabetes. Here, we show that Caenorhabditis elegans oga-1 encodes an active O-GlcNAcase. We also describe a knockout allele, oga-1(ok1207), that is viable and fertile yet accumulates OGlcNAc on nuclear pores and other cellular proteins. Interfering with O-GlcNAc cycling with either oga-1(ok1207) or the O-GlcNAc transferase-null ogt-1(ok430) altered Ser- and Thr-phosphoprotein profiles and increased glycogen synthase kinase 3 beta (GSK-3 beta) levels. Both the oga-1(ok1207) and ogt-1(ok430) strains showed elevated stores of glycogen and trehalose, and decreased lipid storage. These striking metabolic changes prompted us to examine the insulin-like signaling pathway controlling nutrient storage, longevity, and dauer formation in the C elegans O-GlcNAc cycling mutants. Indeed, we found that the oga-1(ok1207) knockout augmented dauer formation induced by a temperature sensitive insulin-like receptor (daf-2) mutant under conditions in which the ogt-1(ok430)-null diminished dauer formation. Our findings suggest that the enzymes of O-GlcNAc cycling "finetune" insulin-like signaling in response to nutrient flux. The knockout of O-GlcNAcase (oga-1) in C elegans mimics many of the metabolic and signaling changes associated with human insulin resistance and provides a genetically amenable model of non-insulin-dependent diabetes.