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 ␤ subunit of AMPK to regulate its steady-state protein levels. Other investigators found that AMPK regulatory components, including the AMPK ␣ 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. The 5=-AMP-activated protein kinase (AMPK) functions as a metabolic fuel gauge that is activated in response to numerous environmental stressors to restore cellular and whole-body energy balance.1,2 AMPK is allosterically regulated by the competitive binding of AMP and ATP, thereby "sensing" cellular energy status and, on activation, triggers compensatory ATP-generating mechanisms while attenuating ATP-consuming processes.3 Perturbations in cardiac metabolism are closely linked to the onset and progression of cardiovascular diseases; given the central role of AMPK in regulating cellular energetics, there is considerable interest in the determination of the precise role(s) of AMPK in cardiac pathophysiological states and evaluation of the utility of modulating AMPK activity as a therapeutic intervention. 4 This review discusses AMPK function in normal and diseased hearts, with emphases on AMPK and protein degradation via the ubiquitin proteasome pathway-a potential novel approach to treating cardiovascular disease. These are significant new findings as ubiquitination is emerging as a pivotal regulatory mechanism that rivals phosphorylation in its overall significance in biology. 5 Structure and Regulation of AMPKAMPK is a highly conserved heterotrimeric enzyme consisting of three subunits, ␣, ␤, and ␥, with multiple genes encoding distinct subunit isoforms (ie, ␣1, ␣2, ␤1, ␤2, ␥1, ␥2, and ␥3). The structure and r...

E3 Ubiquitin Ligase, WWP1, Interacts with AMPKα2 and Down-regulates Its Expression in Skeletal Muscle C2C12 Cells

“…These results demonstrate that WWP1 has an important role in glucose homeostasis through regulating AMPK␣2 expression. Regulation of AMPK by ubiquitination has been suggested (29,30). The AMPK kinases NUAK1 and MARK4 are polyubiquitinated, and expression of NUAK and MARK4 mutants did not interact with the de-ubiquitinating enzyme USP9X de-ubiquitinating enzyme (DUB), thus resulting in AMPK activity (18).…”

The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span

“…Further layers of regulatory finesse include the reversible physical allosteric association between the ␣ and ␥ regulatory subunits and the nuclear translocation of the active trimeric complex to alter gene expression that aims to preserve the energy balance of the cell (10,20,22). Also conserved is acetylation and ubiquitination, recently reported for both mammalian AMPK and yeast SNF1 kinase complexes (23)(24)(25)(26), that appear to have inhibitory roles in regulation of the kinase. Similarly, SUMOylation has been shown to be a negative regulator of Snf1 (27), clearly adding to the complexity of regulation of this central energy-sensing switch.…”

Knockdown of AT-rich interaction domain (ARID) 5B gene expression induced AMPKα2 activation in cardiac myocytes

“…Another study showed that life-long CR elicits a myocardial phenotype that is profoundly protected against ischemia/reperfusion injury, and that AMPK activation may play an important role in this process (33). It has been suggested that ubiquitination of AMPK in the heart may play a significant role in the etiology of cardiac diseases, and that this process presents an attractive target for developing novel therapies (34). In this regard, our finding that ARID5B may de-stabilize AMPKα2 protein in cardiomyocytes is intriguing.…”