Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy.
Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy.
复制标题
伸长因子2激酶通过抑制蛋白质合成而无需诱导自噬来促进细胞存活。
DOI：
10.1016/j.cellsig.2016.01.005
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发表时间：
2016-04
影响因子：
4.8
通讯作者：
Proud CG
中科院分区：
文献类型：
--
作者：
Moore CE;Wang X;Xie J;Pickford J;Barron J;Regufe da Mota S;Versele M;Proud CG
真核细胞延伸因子2激酶（eEF 2K）通过磷酸化其唯一已知的底物eEF 2来抑制蛋白质合成的延伸阶段。eEF 2K受营养敏感信号通路的严格调控。例如，它通过经由雷帕霉素复合物1（mTORC 1）的哺乳动物靶点的信号传导而被抑制。因此，它在营养缺乏的条件下被激活。在这里，我们表明，抑制eEF 2K或敲低其表达使癌细胞在营养缺乏条件下对死亡敏感，并且这是通过阻断蛋白质合成的化合物来拯救的。这意味着eEF 2K通过抑制蛋白质合成来保护营养缺乏的细胞。其中通过mTORC 1的信号传导是高度活跃的细胞对营养素戒断非常敏感。抑制mTORC 1可以保护它们。我们的数据显示，eEF 2K对mTORC 1抑制的细胞保护作用有实质性贡献。eEF 2K还被报道促进另一种潜在的细胞保护过程，自噬。我们已经使用了几种方法来测试在各种条件下eEF 2K的抑制或缺失是否会影响自噬。我们没有发现证据表明eEF 2K参与了我们研究的细胞类型中的自噬激活。我们的结论是，eEF 2K通过抑制蛋白质合成而不是激活自噬来保护癌细胞免受营养饥饿。真核延伸因子-2激酶帮助癌细胞在营养饥饿中存活，是一个有吸引力的抗癌靶点。据报道，eEF 2K促进自噬;然而，我们的证据表明eEF 2K不调节自噬。eEF 2K通过抑制蛋白质合成来保护细胞。
Eukaryotic elongation factor 2 kinase (eEF2K) inhibits the elongation stage of protein synthesis by phosphorylating its only known substrate, eEF2. eEF2K is tightly regulated by nutrient-sensitive signalling pathways. For example, it is inhibited by signalling through mammalian target of rapamycin complex 1 (mTORC1). It is therefore activated under conditions of nutrient deficiency. Here we show that inhibiting eEF2K or knocking down its expression renders cancer cells sensitive to death under nutrient-starved conditions, and that this is rescued by compounds that block protein synthesis. This implies that eEF2K protects nutrient-deprived cells by inhibiting protein synthesis. Cells in which signalling through mTORC1 is highly active are very sensitive to nutrient withdrawal. Inhibiting mTORC1 protects them. Our data reveal that eEF2K makes a substantial contribution to the cytoprotective effect of mTORC1 inhibition. eEF2K is also reported to promote another potentially cytoprotective process, autophagy. We have used several approaches to test whether inhibition or loss of eEF2K affects autophagy under a variety of conditions. We find no evidence that eEF2K is involved in the activation of autophagy in the cell types we have studied. We conclude that eEF2K protects cancer cells against nutrient starvation by inhibiting protein synthesis rather than by activating autophagy. Eukaryotic elongation factor-2 kinase helps cancer cells survive nutrient starvation and is an attractive anti-cancer target. eEF2K has been reported to promote autophagy; however, our evidence shows eEF2K does not modulate autophagy. eEF2K protects cells by inhibiting protein synthesis.