CHIP protects against cardiac pressure overload through regulation of AMPK.
J Clin Invest, 2013/8;123(8):3588-99.
Schisler JC[1], Rubel CE, Zhang C, Lockyer P, Cyr DM, Patterson C
Affiliations
PMID: 23863712
Impact factor: 19.456
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.
MeSH terms
AMP-Activated Protein Kinases; Amino Acid Sequence; Animals; COS Cells; Cardiomegaly; Catalytic Domain; Chlorocebus aethiops; Energy Metabolism; Enzyme Activation; Female; Gene Expression; Gene Expression Regulation, Enzymologic; Male; Mice; Mice, Knockout; Mitochondria, Heart; Mitochondrial Turnover; Molecular Sequence Data; Multigene Family; Myocardium; Protein Binding; Protein Subunits; Signal Transduction; Ubiquitin-Protein Ligases; Ventricular Pressure
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