1. CHIP protects against cardiac pressure overload through regulation of AMPK
- Author
-
Cam Patterson, Jonathan C. Schisler, Douglas M. Cyr, Pamela Lockyer, Chunlian Zhang, and Carrie E. Rubel
- Subjects
Male ,Cardiac function curve ,medicine.medical_specialty ,Ubiquitin-Protein Ligases ,Molecular Sequence Data ,Regulator ,Gene Expression ,Cardiomegaly ,AMP-Activated Protein Kinases ,Biology ,Mitochondrion ,Gene Expression Regulation, Enzymologic ,Mitochondria, Heart ,Mice ,Enzyme activator ,Catalytic Domain ,Internal medicine ,Chlorocebus aethiops ,Ventricular Pressure ,medicine ,Animals ,Amino Acid Sequence ,Mice, Knockout ,Pressure overload ,Myocardium ,AMPK ,Mitochondrial Turnover ,General Medicine ,Cell biology ,Enzyme Activation ,Protein Subunits ,Endocrinology ,Multigene Family ,COS Cells ,Phosphorylation ,Female ,Signal transduction ,Energy Metabolism ,Research Article ,Protein Binding ,Signal Transduction - Abstract
Protein quality control and metabolic homeostasis are integral to maintaining cardiac function during stress; however, little is known about if or how these systems interact. Here we demonstrate that C terminus of HSC70-interacting protein (CHIP), a regulator of protein quality control, influences the metabolic response to pressure overload by direct regulation of the catalytic α subunit of AMPK. Induction of cardiac pressure overload in Chip-/- mice resulted in robust hypertrophy and decreased cardiac function and energy generation stemming from a failure to activate AMPK. Mechanistically, CHIP promoted LKB1-mediated phosphorylation of AMPK, increased the specific activity of AMPK, and was necessary and sufficient for stress-dependent activation of AMPK. CHIP-dependent effects on AMPK activity were accompanied by conformational changes specific to the α subunit, both in vitro and in vivo, identifying AMPK as the first physiological substrate for CHIP chaperone activity and establishing a link between cardiac proteolytic and metabolic pathways.
- Published
- 2013
- Full Text
- View/download PDF