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.
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Seung Baek
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Huadong
authors.initials: H
authors.lastname: Pei
authors.affiliation: Department of Pharmacology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: Wang.Liewei@mayo.edu.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: Lou.Zhenkun@mayo.edu.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D004789:Enzyme Activation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000737:chemistry* / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C431363:USP10 protein, human; C579090:USP10 protein, mouse; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D043222:Ubiquitin Thiolesterase