title: CHIP protects against cardiac pressure overload through regulation of AMPK.
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.
authors.affiliation: McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7126, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Rubel
authors.forename: Chunlian
authors.initials: C
authors.lastname: Zhang
authors.forename: Pamela
authors.initials: P
authors.lastname: Lockyer
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cyr
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D006332:Cardiomegaly / Q000201:enzymology* / Q000503:physiopathology; D020134:Catalytic Domain; D002522:Chlorocebus aethiops; D004734:Energy Metabolism / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000473:pathology; D063269:Mitochondrial Turnover; D008969:Molecular Sequence Data; D005810:Multigene Family; D009206:Myocardium / Q000473:pathology; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D017725:Ventricular Pressure
chemical_list: D021122:Protein Subunits; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases