MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Cancer Center, Zhejiang University, Hangzhou 310058, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Mol Cell. 2022 Dec 15;82(24):4700-4711.e12. doi: 10.1016/j.molcel.2022.10.030. Epub 2022 Nov 15.
Maintenance of energy level to drive movements and material exchange with the environment is a basic principle of life. AMP-activated protein kinase (AMPK) senses energy level and is a major regulator of cellular energy responses. The gamma subunit of AMPK senses elevated ratio of AMP to ATP and allosterically activates the alpha catalytic subunit to phosphorylate downstream effectors. Here, we report that knockout of AMPKγ, but not AMPKα, suppressed phosphorylation of eukaryotic translation elongation factor 2 (eEF2) induced by energy starvation. We identified PPP6C as an AMPKγ-regulated phosphatase of eEF2. AMP-bound AMPKγ sequesters PPP6C, thereby blocking dephosphorylation of eEF2 and thus inhibiting translation elongation to preserve energy and to promote cell survival. Further phosphoproteomic analysis identified additional targets of PPP6C regulated by energy stress in an AMPKγ-dependent manner. Thus, AMPKγ senses cellular energy availability to regulate not only AMPKα kinase, but also PPP6C phosphatase and possibly other effectors.
维持能量水平以驱动运动和与环境进行物质交换是生命的基本原理。AMP 激活的蛋白激酶（AMPK）感知能量水平，是细胞能量反应的主要调节剂。AMPK 的γ亚基感知 AMP 与 ATP 的比值升高，并变构激活α催化亚基，磷酸化下游效应物。在这里，我们报告 AMPKγ 的敲除，而不是 AMPKα 的敲除，抑制了能量饥饿诱导的真核翻译延伸因子 2（eEF2）的磷酸化。我们鉴定出 PPP6C 是 AMPKγ 调节的 eEF2 的磷酸酶。AMP 结合的 AMPKγ 将 PPP6C 隔离，从而阻止 eEF2 的去磷酸化，从而抑制翻译延伸以保存能量并促进细胞存活。进一步的磷酸蛋白质组学分析鉴定出在 AMPKγ 依赖性方式下，能量应激调节的 PPP6C 的其他靶标。因此，AMPKγ 感知细胞能量可用性，不仅调节 AMPKα 激酶，还调节 PPP6C 磷酸酶，并且可能还有其他效应物。
