@article{582db839cf864ddb842df356249ce689,
title = "Deubiquitination and Activation of AMPK by USP10",
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.",
author = "Min Deng and Xu Yang and Bo Qin and Tongzheng Liu and Haoxing Zhang and Wei Guo and Lee, {Seung Baek} and Kim, {Jung Jin} and Jian Yuan and Huadong Pei and Liewei Wang and Zhenkun Lou",
note = "Funding Information: This work was supported by the grants from National Basic Research Program of China (nos. 2013CB910300, 2012CB910300, and 2015CB910600 to H.D.P. and 2013CB530700 to J.Y.), National Natural Science Foundation of China (no. 31571463, 81572740, 81402295, and 31371433 to H. P. and 81222029 and 31270806 to J.Y.), Natural Science Foundation of Beijing (no. 5152009 to H.P.), International S&T Cooperation Program of China (no. 2015DFA31680 to H.P. and 2015DFA30610 to Z.L.), state Key Laboratory of Proteomics (no. SKLP-O201303 to H.P), One Thousand Young Talent Program to H.P and NIH grants (CA130996, CA189666, CA129344, and CA148940 to Z.L. and CA196648 to L.W.). We thank Dr. Eduardo N. Chini for providing WT or AMPKα1 - and AMPKα2 -deficient MEFs ( ampkα −/− ). We thank Debra Evans for proofreading the manuscript. Funding Information: This work was supported by the grants from National Basic Research Program of China (nos. 2013CB910300, 2012CB910300, and 2015CB910600 to H.D.P. and 2013CB530700 to J.Y.), National Natural Science Foundation of China (no. 31571463, 81572740, 81402295, and 31371433 to H. P. and 81222029 and 31270806 to J.Y.), Natural Science Foundation of Beijing (no. 5152009 to H.P.), International S&T Cooperation Program of China (no. 2015DFA31680 to H.P. and 2015DFA30610 to Z.L.), state Key Laboratory of Proteomics (no. SKLP-O201303 to H.P), One Thousand Young Talent Program to H.P and NIH grants (CA130996, CA189666, CA129344, and CA148940 to Z.L. and CA196648 to L.W.). We thank Dr. Eduardo N. Chini for providing WT or AMPKa1- and AMPKa2-deficient MEFs (ampka-/-). We thank Debra Evans for proofreading the manuscript. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = feb,
day = "18",
doi = "10.1016/j.molcel.2016.01.010",
language = "English (US)",
volume = "61",
pages = "614--624",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}