CHIP protects against cardiac pressure overload through regulation of AMPK.
J Clin Invest
; 123(8): 3588-99, 2013 Aug.
Article
en En
| MEDLINE
| ID: mdl-23863712
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Cardiomegalia
/
Presión Ventricular
/
Ubiquitina-Proteína Ligasas
/
Proteínas Quinasas Activadas por AMP
Límite:
Animals
Idioma:
En
Revista:
J Clin Invest
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos