Abstract
The regulatory control of cardiac endoplasmic reticulum (ER) stress is incompletely characterized. As ER stress signaling upregulates the E3-ubiquitin ligase Parkin, we investigated the role of Parkin in cardiac ER stress. Parkin knockout mice exposed to aortic constriction-induced cardiac pressure-overload or in response to systemic tunicamycin (TM) developed adverse ventricular remodeling with excessive levels of the ER regulatory C/EBP homologous protein CHOP. CHOP was identified as a Parkin substrate and its turnover was Parkin-dose and proteasome-dependent. Parkin depletion in cardiac HL-1 cells increased CHOP levels and enhanced susceptibility to TM-induced cell death. Parkin reconstitution rescued this phenotype and the contribution of excess CHOP to this ER stress injury was confirmed by reduction in TM-induced cell death when CHOP was depleted in Parkin knockdown cardiomyocytes. Isogenic Parkin mutant iPSC-derived cardiomyocytes showed exaggerated ER stress induced CHOP and apoptotic signatures and myocardium from subjects with dilated cardiomyopathy showed excessive Parkin and CHOP induction. This study identifies that Parkin functions to blunt excessive CHOP to prevent maladaptive ER stress-induced cell death and adverse cardiac ventricular remodeling. Additionally, Parkin is identified as a novel post-translational regulatory moderator of CHOP stability and uncovers an additional stress-modifying function of this E3-ubiquitin ligase.
Highlights
The E3-ubiquitin ligase Parkin is enriched in multiple organs[1, 2], resides in various subcellular locations[3, 4] and its cognate ubiquitylation substrates modulate diverse cellular functions spanning from the regulation of gene transcription, protein stability, endoplasmic reticulum (ER) stress and mitochondrial quality control[5,6,7,8]
We found that Parkin levels were robustly increased following thoracic aortic constriction (TAC) in wild type (WT) mice and that Parkin deficient mice exhibit exaggerated cardiac hypertrophy and contractile dysfunction in response to TAC
In concert with prior studies that implicate a role for Parkin in the control of ER biology, we showed that the absence of Parkin exacerbated adverse pressure-overload induced cardiac remodeling and evoked excess myocardial ER stress and apoptotic signatures
Summary
The E3-ubiquitin ligase Parkin is enriched in multiple organs[1, 2], resides in various subcellular locations[3, 4] and its cognate ubiquitylation substrates modulate diverse cellular functions spanning from the regulation of gene transcription, protein stability, endoplasmic reticulum (ER) stress and mitochondrial quality control[5,6,7,8]. We reasoned that cardiac pressure-overload biomechanical stress would be an additional pathology, to enable characterization of chronic Parkin-linked adaptive and/or maladaptive programming. We found that Parkin levels were robustly increased following TAC in wild type (WT) mice and that Parkin deficient mice exhibit exaggerated cardiac hypertrophy and contractile dysfunction in response to TAC In parallel to this adverse remodeling, the C/EBP homologous protein (CHOP), a known regulator of ER stress initiated apoptosis, was disproportionally increased in Parkin KO mice. Excess ER stress was evident in human primary fibroblasts from subjects with genetic mutations in PARK2 and in Parkin deficient iPSC-derived cardiomyocytes Together these data show that Parkin modulates ER stress via the post-translational control of CHOP levels to blunt adverse remodeling in response to pressure-overload and in response to systemic ER stress
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