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Mol Cell. 2016 Feb 18;61(4):614-624. doi: 10.1016/j.molcel.2016.01.010. Epub 2016 Feb 11.

Deubiquitination and Activation of AMPK by USP10.

Author information

1
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
2
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
3
Department of Pharmacology, Mayo Clinic, Rochester, MN 55905, USA.
4
Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China.
5
Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.
6
Department of Pharmacology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: Wang.Liewei@mayo.edu.
7
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: Lou.Zhenkun@mayo.edu.

Abstract

The AMP-activated protein kinase (AMPK) is the master regulator of metabolic homeostasis by sensing cellular energy status. When intracellular ATP levels decrease during energy stress, AMPK is initially activated through AMP or ADP binding and phosphorylation of a threonine residue (Thr-172) within the activation loop of its kinase domain. Here we report a key molecular mechanism by which AMPK activation is amplified under energy stress. We found that ubiquitination on AMPKα blocks AMPKα phosphorylation by LKB1. The deubiquitinase USP10 specifically removes ubiquitination on AMPKα to facilitate AMPKα phosphorylation by LKB1. Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10. Thus, USP10 and AMPK form a key feedforward loop ensuring amplification of AMPK activation in response to fluctuation of cellular energy status. Disruption of this feedforward loop leads to improper AMPK activation and multiple metabolic defects.

PMID:
26876938
PMCID:
PMC4836875
DOI:
10.1016/j.molcel.2016.01.010
[Indexed for MEDLINE]
Free PMC Article

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