Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress

Scientific Reports
Kim HanMichael N Sack

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 adv...Continue Reading

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Citations

Dec 13, 2018·Physiological Reviews·Åsa B Gustafsson, Gerald W Dorn
Oct 28, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yingqing ChenHun Taeg Chung
Sep 23, 2018·Scientific Reports·Alessandra MatteucciTito Calì
Sep 30, 2017·Frontiers in Pharmacology·Xiaojuan QieChunling Ma
Feb 16, 2021·Frontiers in Cell and Developmental Biology·Shuang LiuBo Zhang
Feb 12, 2021·Biochimica Et Biophysica Acta. General Subjects·Swagatika Paul, Alicia M Pickrell
Feb 7, 2021·International Journal of Molecular Sciences·Junyan QuZhenghong Lin
Apr 24, 2021·Scientific Reports·Kana MiyaharaKeisuke Miyazawa
Sep 30, 2021·Molecular and Cellular Biochemistry·Sudhir PandeyChih-Yang Huang

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Methods Mentioned

BETA
electron microscopy
co-immunoprecipitation
immunoprecipition
pull-down
immunoprecipitation
flow cytometry
transfection
protein folding
dissection
PCR

Software Mentioned

CAAS MRV FARM

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