Energy sensor AMPK gamma regulates translation via phosphatase PPP6C independent of AMPK alpha

Qi Zhou; Bingbing Hao; Xiaolei Cao; Lin Gao; Zhenyue Yu; Yang Zhao; Mingrui Zhu; Guoxuan Zhong; Fangtao Chi; Xiaoming Dai; Jizhong Mao; Yibing Zhu; Ping Rong; Liang Chen; Xueli Bai; Cunqi Ye; Shuai Chen; Tingbo Liang; Li Li; Xin-Hua Feng; Minjia Tan; Bin Zhao

doi:10.1016/j.molcel.2022.10.030

Energy sensor AMPK gamma regulates translation via phosphatase PPP6C independent of AMPK alpha

Mol Cell. 2022 Dec 15;82(24):4700-4711.e12. doi: 10.1016/j.molcel.2022.10.030. Epub 2022 Nov 15.

Authors

Qi Zhou¹, Bingbing Hao², Xiaolei Cao¹, Lin Gao¹, Zhenyue Yu¹, Yang Zhao¹, Mingrui Zhu², Guoxuan Zhong¹, Fangtao Chi³, Xiaoming Dai³, Jizhong Mao³, Yibing Zhu³, Ping Rong⁴, Liang Chen⁴, Xueli Bai⁵, Cunqi Ye³, Shuai Chen⁴, Tingbo Liang⁵, Li Li⁶, Xin-Hua Feng⁷, Minjia Tan⁸, Bin Zhao⁹

Affiliations

¹ 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.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ 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.
⁴ MOE Key Laboratory of Model Animal for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University, Nanjing 210061, China.
⁵ Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China.
⁶ Institute of Aging Research, Hangzhou Normal University, Hangzhou 311121, China.
⁷ 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. Electronic address: xhfeng@zju.edu.cn.
⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: mjtan@simm.ac.cn.
⁹ 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; Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing 321000, China. Electronic address: binzhao@zju.edu.cn.

PMID: 36384136
DOI: 10.1016/j.molcel.2022.10.030

Abstract

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.

Keywords: AMPK; PPP6C; eEF2; energy level; phosphorylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases* / genetics
AMP-Activated Protein Kinases* / metabolism
Peptide Elongation Factor 2 / metabolism
Phosphorylation
Protein Biosynthesis*

Substances

AMP-Activated Protein Kinases
Peptide Elongation Factor 2