title: Regulation of AMPK by the ubiquitin proteasome system.
abstract: The 5'-AMP-activated protein kinase (AMPK) functions as a metabolic fuel gauge that is activated in response to environmental stressors to restore cellular energy balance. In the heart, AMPK coordinates the activation of glucose and fatty acid metabolic pathways to ensure increased production of myocardial ATP when required, such as during cardiac ischemia/reperfusion and hypertrophy, causing an increase in AMPK activity that can be viewed as both protective and maladaptive. While we understand the basic regulation of AMPK activity by kinases, recent studies have introduced the concept that AMPK is regulated by other post-translational modifications, specifically ubiquitination. These studies reported that the ubiquitin ligase cell death-inducing DFFA-like effector a ubiquitinates the β subunit of AMPK to regulate its steady-state protein levels. Other investigators found that AMPK regulatory components, including the AMPK α subunit and AMPK kinases NUAK1 and MARK4, can be ubiquitinated with atypical ubiquitin chains. The USP9X-deubiquitinating enzyme was identified to remove ubiquitination from both NUAK1 and MARK4. Lastly, AMPK activation increases the expression of the ubiquitin ligases MAFBx/Atrogin-1 and MuRF1. These ubiquitin ligases regulate key cardiac transcription factors to control cardiomyocyte mass and remodeling, thus suggesting another mechanism by which AMPK may function in the heart. The relevance of AMPK ubiquitination in cardiac disease has yet to be tested directly, but it likely represents an important mechanism that occurs in common cardiac diseases that may be targeted for therapy.
authors.affiliation: Discipline of Human Physiology, University of KwaZulu Natal, Durban, South Africa.
authors.forename: Makhosazane
authors.initials: M
authors.lastname: Zungu
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.forename: M Faadiel
authors.initials: MF
authors.lastname: Essop
authors.forename: Chris
authors.initials: C
authors.lastname: McCudden
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D006331:Heart Diseases / Q000201:enzymology*; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D046988:Proteasome Endopeptidase Complex