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CHIP protects against cardiac pressure overload through regulation of AMPK.

Authors
  • Schisler, Jonathan C
  • Rubel, Carrie E
  • Zhang, Chunlian
  • Lockyer, Pamela
  • Cyr, Douglas M
  • Patterson, Cam
Type
Published Article
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Publication Date
Aug 01, 2013
Volume
123
Issue
8
Pages
3588–3599
Identifiers
DOI: 10.1172/JCI69080
PMID: 23863712
Source
Medline
License
Unknown

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.

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