| First Author | Schisler JC | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 8 | Pages | 3588-99 |
| PubMed ID | 23863712 | Mgi Jnum | J:201409 |
| Mgi Id | MGI:5514077 | Doi | 10.1172/JCI69080 |
| Citation | Schisler JC, et al. (2013) CHIP protects against cardiac pressure overload through regulation of AMPK. J Clin Invest 123(8):3588-99 |
| abstractText | 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 alpha 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 alpha 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. |
