Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress

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...

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Autores principales:	Kim Han, Shahin Hassanzadeh, Komudi Singh, Sara Menazza, Tiffany T. Nguyen, Mark V. Stevens, An Nguyen, Hong San, Stasia A. Anderson, Yongshun Lin, Jizhong Zou, Elizabeth Murphy, Michael N. Sack
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e74432eb6d7b4605b5186f619f445cc1
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spelling	oai:doaj.org-article:e74432eb6d7b4605b5186f619f445cc12021-12-02T16:06:22ZParkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress10.1038/s41598-017-02339-22045-2322https://doaj.org/article/e74432eb6d7b4605b5186f619f445cc12017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02339-2https://doaj.org/toc/2045-2322Abstract 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.Kim HanShahin HassanzadehKomudi SinghSara MenazzaTiffany T. NguyenMark V. StevensAn NguyenHong SanStasia A. AndersonYongshun LinJizhong ZouElizabeth MurphyMichael N. SackNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kim Han Shahin Hassanzadeh Komudi Singh Sara Menazza Tiffany T. Nguyen Mark V. Stevens An Nguyen Hong San Stasia A. Anderson Yongshun Lin Jizhong Zou Elizabeth Murphy Michael N. Sack Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress
description	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.
format	article
author	Kim Han Shahin Hassanzadeh Komudi Singh Sara Menazza Tiffany T. Nguyen Mark V. Stevens An Nguyen Hong San Stasia A. Anderson Yongshun Lin Jizhong Zou Elizabeth Murphy Michael N. Sack
author_facet	Kim Han Shahin Hassanzadeh Komudi Singh Sara Menazza Tiffany T. Nguyen Mark V. Stevens An Nguyen Hong San Stasia A. Anderson Yongshun Lin Jizhong Zou Elizabeth Murphy Michael N. Sack
author_sort	Kim Han
title	Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress
title_short	Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress
title_full	Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress
title_fullStr	Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress
title_full_unstemmed	Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress
title_sort	parkin regulation of chop modulates susceptibility to cardiac endoplasmic reticulum stress
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e74432eb6d7b4605b5186f619f445cc1
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_version_	1718385062640091136

Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress

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