Increased glutamine catabolism mediates bone anabolism in response to WNT signaling
Increased glutamine catabolism mediates bone anabolism in response to WNT signaling
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DOI：
10.1172/jci78470
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发表时间：
2015-02-01
影响因子：
15.9
通讯作者：
Long, Fanxin
中科院分区：
文献类型：
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作者：
Karner, Courtney M.;Esen, Emel;Long, Fanxin
WNT 信号通过增加成骨细胞的数量及其蛋白质合成活性来刺激骨形成。目前尚不清楚 WNT 如何增强成骨细胞祖细胞的能力，以满足与成熟成骨细胞相关的能量和合成需求的增加。在这里，在培养的成骨细胞祖细胞中，我们确定 WNT 通过三羧酸 (TCA) 循环刺激谷氨酰胺分解代谢，从而降低细胞内谷氨酰胺水平。 WNT 诱导的谷氨酰胺浓度降低触发了一般控制的不可抑制性 2 介导的（GCN2 介导的）整合应激反应 (ISR)，刺激负责氨基酸供应、转移 RNA (tRNA) 氨酰化和蛋白质折叠的基因表达。 WNT 诱导的谷氨酰胺分解代谢和 ISR 与 p-连环蛋白无关，但需要哺乳动物靶点雷帕霉素复合物 1 (mTORC1) 激活。在人类骨硬化症 WNT 信号传导过度活跃的小鼠模型中，抑制谷氨酰胺分解代谢或删除 Gcn2 可抑制过度的骨形成。总之，我们的数据表明，谷氨酰胺既是一种能源，又是一种对 WNT 敏感的蛋白质翻译变阻器，并表明操纵谷氨酰胺/GCN2 信号轴可能为使与人类疾病相关的紊乱蛋白质合成代谢正常化提供有价值的方法。
WNT signaling stimulates bone formation by increasing both the number of osteoblasts and their protein-synthesis activity. It is not clear how WNT augments the capacity of osteoblast progenitors to meet the increased energetic and synthetic needs associated with mature osteoblasts. Here, in cultured osteoblast progenitors, we determined that WNT stimulates glutamine catabolism through the tricarboxylic acid (TCA) cycle and consequently lowers intracellular glutamine levels. The WNT-induced reduction of glutamine concentration triggered a general control nonderepressible 2-mediated (GCN2-mediated) integrated stress response (ISR) that stimulated expression of genes responsible for amino acid supply, transfer RNA (tRNA) aminoacylation, and protein folding. WNT-induced glutamine catabolism and ISR were p-catenin independent, but required mammalian target of rapamycin complex 1 (mTORC1) activation. In a hyperactive WNT signaling mouse model of human osteosclerosis, inhibition of glutamine catabolism or Gcn2 deletion suppressed excessive bone formation. Together, our data indicate that glutamine is both an energy source and a protein-translation rheostat that is responsive to WNT and suggest that manipulation of the glutamine/GCN2 signaling axis may provide a valuable approach for normalizing deranged protein anabolism associated with human diseases.