CHIP protects against cardiac pressure overload through regulation of AMPK
Jonathan C. Schisler, … , Douglas M. Cyr, Cam Patterson
Jonathan C. Schisler, … , Douglas M. Cyr, Cam Patterson
Published July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3588-3599. https://doi.org/10.1172/JCI69080.
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Research Article Cardiology

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

Jonathan C. Schisler, Carrie E. Rubel, Chunlian Zhang, Pamela Lockyer, Douglas M. Cyr, Cam Patterson

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Figure 6

Proposed physiological model for the CHIP-dependent effects on the regulation of AMPK function.

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Proposed physiological model for the CHIP-dependent effects on the regul...
In unstressed conditions, CHIP forms a complex that contains the AMPK holoenzyme; however, the consequence of this interaction is not understood, as CHIP does not appear to directly affect either baseline AMPK activation status, depicted by phosphorylation at α-T172 (P), or baseline AMPK activity (indicated by the star). In cell stress conditions, such as oxidative stress and cardiac pressure overload, or in the presence of AMPK agonists, CHIP is necessary for LKB1-mediated activation of AMPK, as observed by increased phosphorylation of the α (catalytic) subunit, which leads to an increase in AMPK activity. In addition to increasing LKB1-mediated phosphorylation of AMPK, in cell-free systems, CHIP robustly increases AMPK activity independent of phosphorylation, acting as a chaperone of AMPK, amplifying the positive effect of CHIP on AMPK activity. CHIP may also play a key role in the recovery phase in returning the cell to metabolic homeostasis. CHIP mediates polyubiquitination of LKB1, leading to degradation of LKB1 via a proteasome-dependent mechanism that may contribute to restoring AMPK activation status to baseline levels.