Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure.
Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure.
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DOI：
10.1016/j.celrep.2015.11.020
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发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Bernal-Mizrachi E
中科院分区：
文献类型：
--
作者：
Alejandro EU;Bozadjieva N;Kumusoglu D;Abdulhamid S;Levine H;Haataja L;Vadrevu S;Satin LS;Arvan P;Bernal-Mizrachi E
营养水平决定了O-linked N-acetylglucosamine Transferase （OGT）的活性，以调节o - glcn酰化，这是一种翻译后修饰机制，可“微调”细胞内信号传导和代谢状态。然而，o - glcn酰化通过调节胰腺β细胞的质量和功能来维持葡萄糖稳态的需要尚不清楚。在这里，我们揭示了缺乏β细胞OGT （βOGT-KO）的小鼠发生糖尿病和β细胞衰竭。βOGT-KO小鼠表现出内质网应激增加和内质网结构膨胀，这些变化最终导致内质网应激诱导的β细胞凋亡和增殖减少。Akt1/2信号在βOGT-KO胰岛中也受到抑制。通过修复伴有Chop基因缺失或Akt2基因重构的βOGT-KO小鼠的表型，证明了这些过程的机制作用。这些发现表明，OGT是β细胞质量和功能的调节剂，并通过调节内质网应激反应和调节Akt1/2信号，提供了o - glcn酰化与β细胞存活之间的直接联系。
Nutrient levels dictate the activity of O-linked N-acetylglucosamine Transferase (OGT) to regulate O-GlcNAcylation, a post-translational modification mechanism to “fine-tune” intracellular signaling and metabolic status. However, the requirement of O-GlcNAcylation for maintaining glucose homeostasis by regulating pancreatic β-cell mass and function is unclear. Here, we reveal that mice lacking β-cell OGT (βOGT-KO) develop diabetes and β-cell failure. βOGT-KO mice demonstrated increased ER stress and distended ER architecture, and these changes ultimately cause the loss of β-cell mass due to ER stress-induced apoptosis and decreased proliferation. Akt1/2 signaling was also dampened in βOGT-KO islets. The mechanistic role of these processes was demonstrated by rescuing the phenotype of βOGT-KO mice with concomitant Chop gene deletion or genetic reconstitution of Akt2. These findings identify OGT as a regulator of β-cell mass and function, and provide a direct link between O-GlcNAcylation and β-cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling.