ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate.
ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate.
复制标题
DOI：
10.1016/j.molcel.2015.06.020
复制
发表时间：
2015-08-06
期刊：
影响因子：
16
通讯作者：
Yoon SO
中科院分区：
文献类型：
--
作者：
Shin S;Buel GR;Wolgamott L;Plas DR;Asara JM;Blenis J;Yoon SO
营养不足会破坏生理平衡，导致疾病甚至死亡。考虑到这种代谢应激的生理和病理后果，细胞在这种条件下利用的适应性反应引起了极大的兴趣。我们发现，在低葡萄糖条件下，细胞启动适应，然后分别使用PERK/Akt和MEK 1/ERK 2信号转导的凋亡反应。为了适应，细胞参与内质网应激诱导的未折叠蛋白反应，这导致PERK/Akt活化和细胞存活。持续和极端的能量应激促进向亚型特异性MEK 1/ERK 2信号传导的转换，诱导GCN 2/eIF 2 α磷酸化和ATF 4表达，其覆盖PERK/Akt介导的适应，并通过ATF 4依赖性促凋亡因子（包括Bid和Trb 3）的表达诱导凋亡。代谢应激期间ERK 2的激活有助于TCA循环和氨基酸代谢的变化以及细胞死亡，这可通过补充谷氨酸和α-酮戊二酸来抑制。总之，我们的结果揭示了保护细胞或组织免受代谢应激的有希望的靶点。
Insufficient nutrients disrupt physiological homeostasis resulting in diseases and even death. Considering the physiological and pathological consequences of this metabolic stress, the adaptive responses that cells utilize under this condition are of great interest. We show that under low glucose conditions, cells initiate adaptation followed by apoptosis responses using PERK/Akt and MEK1/ERK2 signaling, respectively. For adaptation, cells engage the endoplasmic reticulum stress-induced unfolded protein response, which results in PERK/Akt activation and cell survival. Sustained and extreme energetic stress promotes a switch to isoform-specific MEK1/ERK2 signaling, induction of GCN2/eIF2α phosphorylation and ATF4 expression, which overrides PERK/Akt-mediated adaptation and induces apoptosis through ATF4-dependent expression of pro-apoptotic factors including Bid and Trb3. ERK2 activation during metabolic stress contributes to changes in TCA cycle and amino acid metabolism, and cell death, which is suppressed by glutamate and α-ketoglutarate supplementation. Taken together, our results reveal promising targets to protect cells or tissues from metabolic stress.