Deubiquitination and Activation of AMPK by USP10

Min Deng, Xu Yang, Bo Qin, Tongzheng Liu, Haoxing Zhang, Wei Guo, Seung Baek Lee, Jung Jin Kim, Jian Yuan, Huadong Pei, Liewei Wang, Zhenkun Lou

Research output: Contribution to journalArticle

45 Scopus citations

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. The AMP-activated protein kinase (AMPK) is the master regulator of metabolic homeostasis by sensing cellular energy status. Deng et al. demonstrated AMPK-USP10 forms a positive feedforward loop that ensures amplification of AMPK activation in response to fluctuation of cellular energy status.

Original languageEnglish (US)
Pages (from-to)614-624
Number of pages11
JournalMolecular Cell
Volume61
Issue number4
DOIs
StatePublished - Feb 18 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Deng, M., Yang, X., Qin, B., Liu, T., Zhang, H., Guo, W., Lee, S. B., Kim, J. J., Yuan, J., Pei, H., Wang, L., & Lou, Z. (2016). Deubiquitination and Activation of AMPK by USP10. Molecular Cell, 61(4), 614-624. https://doi.org/10.1016/j.molcel.2016.01.010