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. IntroductionPathological cardiac hypertrophy (subsequently referred to as cardiac hypertrophy) is an adaptive response to increased afterload brought about by hypertension, decreased arterial compliance, and other cardiac stressors (1). During the development of cardiac hypertrophy, numerous cellular processes come into play, including protein synthesis and proteolysis to account for the structural changes that accompany hypertrophy, as well as changes in cardiac metabolism to cope with increased energy demands. Despite the well-known fact that protein turnover and metabolic changes accompany cardiac hypertrophy, surprisingly little is known about how stress-dependent protein quality control mechanisms and metabolic regulation are coordinated, if at all, in the heart. C terminus of HSC70-interacting protein (CHIP, also known as STUB1) is a 35-kDa cytosolic protein initially identified in a screen for proteins that interact with the mammalian chaperones HSC70, HSP70 (2), and HSP90 (3). CHIP is ubiquitously expressed in mammalian tissues but is expressed at highest levels in the adult heart (2). CHIP plays an important dual role as both a cochaperone and a ubiquitin ligase (2-5). More recently, however, an additional role for CHIP in protein quality control has been suggested. Evidence that CHIP can act as an autonomous chaperone, independent of its association with HSPs, has been reported (6). However, these observations were made with a nonphysiological substrate (luciferase), and, to date, verification of CHIP's chaperone activity and identification of a physiological substrate have not been made.Changes in cardiac metabolism, such as oxidative substrate preference, mitochondrial function, and biogenesis, play a key role in the adaptive response to cardiac stress (7). As cardiomyocyte hypertrophy progresses, energy demand increases and cellu-

Tumor suppressor gene ING3 induces cardiomyocyte hypertrophy via inhibition of AMPK and activation of p38 MAPK signaling

“…Previous studies suggested that PE and Akt1-induced hypertrophy in neonatal rat cardiomyocytes are associated with inactivation of AMPK, which may be permissive for protein synthesis and cardiac hypertrophic growth, and activation of AMPK can reverse the PE and Akt1-induced hypertrophic growth [33]. Consistent with this study, adiponectin [34], C terminus of HSC70-interacting protein (CHIP) [35] and Follistatin-like 1 (Fstl1) [36] have been shown to attenuate cardiac hypertrophy through activation of AMPK pathway, while resistin [37] promotes hypertrophic growth via inactivation of an AMPK-dependent signaling mechanism. Further evidence in support of AMPK as an anti-hypertrophic signaling molecule has been provided by other studies, showing that pharmacological activation of AMPK inhibits protein synthesis and attenuates the development of cardiac hypertrophy via inactivation the mTOR pathway [33,38,39].…”

Cardiac ubiquitin ligases: Their role in cardiac metabolism, autophagy, cardioprotection and therapeutic potential

“…In vitro studies revealed that one mechanism CHIP may be regulating autophagy is through its support of Akt signaling to reduce autophagy, whereby CHIP knockdown resulted in and inhibited IGF-1 mediated Akt signaling (and presumably enhanced downstream FOXO1/3 activity) driving increases in the observed autophagic flux 154 . Recent studies have implicated cardiac CHIP in the regulation of AMPK as well 155 . Given the clear link between AMPK and the regulation of autophagy, CHIP may regulate autophagy by multiple mechanisms, including its support of AMPK in a ubiquitin ligases-independent manner 156 , linked to AMPK mTOR regulation 157 .…”

Proteotoxicity and Cardiac Dysfunction

“…179 Recently, in addition to these functions with the UPS, Schisler et al showed that CHIP is required for activation of AMP kinase (AMPK) in response to pressure overload. They identified CHIP as a constituent of the AMPK complex and found decreased AMPK phosphorylation in the absence of CHIP, leading to an exacerbated hypertrophic phenotype 180 AMPK is a known regulator of autophagy, as activated AMPK inhibits mTOR, allowing autophagy to proceed. 181 Proteins such as CHIP, which mediate crosstalk among multiple protective pathways, may prove especially useful for treating proteotoxic diseases of the heart.…”