{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:03:40Z","timestamp":1781658220083,"version":"3.54.5"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T00:00:00Z","timestamp":1495065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T00:00:00Z","timestamp":1495065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.1038\/s41598-017-02339-2","type":"journal-article","created":{"date-parts":[[2017,5,12]],"date-time":"2017-05-12T10:57:28Z","timestamp":1494586648000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress"],"prefix":"10.1038","volume":"7","author":[{"given":"Kim","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahin","family":"Hassanzadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komudi","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Menazza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany T.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark V.","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"San","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stasia A.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongshun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jizhong","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N.","family":"Sack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,18]]},"reference":[{"key":"2339_CR1","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/S0165-3806(01)00234-6","volume":"130","author":"DP Huynh","year":"2001","unstructured":"Huynh, D. P., Dy, M., Nguyen, D., Kiehl, T. R. & Pulst, S. M. Differential expression and tissue distribution of parkin isoforms during mouse development. Brain research. Developmental brain research \n                           130, 173\u2013181, doi:10.1016\/S0165-3806(01)00234-6 (2001).","journal-title":"Brain research. Developmental brain research"},{"key":"2339_CR2","doi-asserted-by":"publisher","first-page":"5956","DOI":"10.1073\/pnas.0931262100","volume":"100","author":"R Cesari","year":"2003","unstructured":"Cesari, R. et al. Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proceedings of the National Academy of Sciences of the United States of America \n                           100, 5956\u20135961, doi:10.1073\/pnas.0931262100 (2003).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"2339_CR3","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1002\/1531-8249(199905)45:5<668::AID-ANA19>3.0.CO;2-Z","volume":"45","author":"H Shimura","year":"1999","unstructured":"Shimura, H. et al. Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients. Annals of neurology \n                           45, 668\u2013672, doi:10.1002\/(ISSN)1531-8249 (1999).","journal-title":"Annals of neurology"},{"key":"2339_CR4","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1083\/jcb.200809125","volume":"183","author":"D Narendra","year":"2008","unstructured":"Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. The Journal of cell biology \n                           183, 795\u2013803, doi:10.1083\/jcb.200809125 (2008).","journal-title":"The Journal of cell biology"},{"key":"2339_CR5","doi-asserted-by":"publisher","first-page":"6283","DOI":"10.1073\/pnas.1113248109","volume":"109","author":"BN Johnson","year":"2012","unstructured":"Johnson, B. N., Berger, A. K., Cortese, G. P. & Lavoie, M. J. The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax. Proceedings of the National Academy of Sciences of the United States of America \n                           109, 6283\u20136288, doi:10.1073\/pnas.1113248109 (2012).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"2339_CR6","doi-asserted-by":"publisher","first-page":"35661","DOI":"10.1074\/jbc.C000447200","volume":"275","author":"Y Imai","year":"2000","unstructured":"Imai, Y., Soda, M. & Takahashi, R. Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. The Journal of biological chemistry \n                           275, 35661\u201335664, doi:10.1074\/jbc.C000447200 (2000).","journal-title":"The Journal of biological chemistry"},{"key":"2339_CR7","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1016\/j.molcel.2013.01.036","volume":"49","author":"AK Muller-Rischart","year":"2013","unstructured":"Muller-Rischart, A. K. et al. The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO. Molecular cell \n                           49, 908\u2013921, doi:10.1016\/j.molcel.2013.01.036 (2013).","journal-title":"Molecular cell"},{"key":"2339_CR8","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.cell.2011.02.010","volume":"144","author":"JH Shin","year":"2011","unstructured":"Shin, J. H. et al. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson\u2019s disease. Cell \n                           144, 689\u2013702, doi:10.1016\/j.cell.2011.02.010 (2011).","journal-title":"Cell"},{"key":"2339_CR9","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/33416","volume":"392","author":"T Kitada","year":"1998","unstructured":"Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature \n                           392, 605\u2013608, doi:10.1038\/33416 (1998).","journal-title":"Nature"},{"key":"2339_CR10","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/nrm3028","volume":"12","author":"RJ Youle","year":"2011","unstructured":"Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nature reviews. Molecular cell biology \n                           12, 9\u201314, doi:10.1038\/nrm3028 (2011).","journal-title":"Nature reviews. Molecular cell biology"},{"key":"2339_CR11","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1074\/jbc.M112.411363","volume":"288","author":"DA Kubli","year":"2013","unstructured":"Kubli, D. A. et al. Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. The Journal of biological chemistry \n                           288, 915\u2013926, doi:10.1074\/jbc.M112.411363 (2013).","journal-title":"The Journal of biological chemistry"},{"key":"2339_CR12","doi-asserted-by":"publisher","first-page":"e20975","DOI":"10.1371\/journal.pone.0020975","volume":"6","author":"C Huang","year":"2011","unstructured":"Huang, C. et al. Preconditioning involves selective mitophagy mediated by Parkin and p62\/SQSTM1. PloS one \n                           6, e20975, doi:10.1371\/journal.pone.0020975 (2011).","journal-title":"PloS one"},{"key":"2339_CR13","doi-asserted-by":"publisher","first-page":"aad2459","DOI":"10.1126\/science.aad2459","volume":"350","author":"G Gong","year":"2015","unstructured":"Gong, G. et al. Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science \n                           350, aad2459\u2013aad2459, doi:10.1126\/science.aad2459 (2015).","journal-title":"Science"},{"key":"2339_CR14","first-page":"387","volume":"79","author":"BJ Maron","year":"1975","unstructured":"Maron, B. J., Ferrans, V. J. & Roberts, W. C. Ultrastructural features of degenerated cardiac muscle cells in patients with cardiac hypertrophy. The American journal of pathology \n                           79, 387\u2013434 (1975).","journal-title":"The American journal of pathology"},{"key":"2339_CR15","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/ncb0311-184","volume":"13","author":"I Tabas","year":"2011","unstructured":"Tabas, I. & Ron, D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nature cell biology \n                           13, 184\u2013190, doi:10.1038\/ncb0311-184 (2011).","journal-title":"Nature cell biology"},{"key":"2339_CR16","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1161\/01.CIR.0000137836.95625.D4","volume":"110","author":"K Okada","year":"2004","unstructured":"Okada, K. et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation \n                           110, 705\u2013712, doi:10.1161\/01.CIR.0000137836.95625.D4 (2004).","journal-title":"Circulation"},{"key":"2339_CR17","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1089\/ars.2006.1522","volume":"9","author":"HQ Wang","year":"2007","unstructured":"Wang, H. Q., Imai, Y., Kataoka, A. & Takahashi, R. Cell type-specific upregulation of Parkin in response to ER stress. Antioxidants & redox signaling \n                           9, 533\u2013542, doi:10.1089\/ars.2006.1522 (2007).","journal-title":"Antioxidants & redox signaling"},{"key":"2339_CR18","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/cdd.2010.142","volume":"18","author":"L Bouman","year":"2011","unstructured":"Bouman, L. et al. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell death and differentiation \n                           18, 769\u2013782, doi:10.1038\/cdd.2010.142 (2011).","journal-title":"Cell death and differentiation"},{"key":"2339_CR19","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/S1097-2765(02)00583-X","volume":"10","author":"Y Imai","year":"2002","unstructured":"Imai, Y. et al. CHIP is associated with Parkin, a gene responsible for familial Parkinson\u2019s disease, and enhances its ubiquitin ligase activity. Molecular cell \n                           10, 55\u201367, doi:10.1016\/S1097-2765(02)00583-X (2002).","journal-title":"Molecular cell"},{"key":"2339_CR20","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1016\/S0092-8674(01)00407-X","volume":"105","author":"Y Imai","year":"2001","unstructured":"Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell \n                           105, 891\u2013902, doi:10.1016\/S0092-8674(01)00407-X (2001).","journal-title":"Cell"},{"key":"2339_CR21","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1161\/CIRCRESAHA.109.213116","volume":"106","author":"T Ago","year":"2010","unstructured":"Ago, T. et al. Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes. Circulation research \n                           106, 1253\u20131264, doi:10.1161\/CIRCRESAHA.109.213116 (2010).","journal-title":"Circulation research"},{"key":"2339_CR22","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1161\/CIRCRESAHA.113.301787","volume":"113","author":"S Sciarretta","year":"2013","unstructured":"Sciarretta, S. et al. Activation of NADPH oxidase 4 in the endoplasmic reticulum promotes cardiomyocyte autophagy and survival during energy stress through the protein kinase RNA-activated-like endoplasmic reticulum kinase\/eukaryotic initiation factor 2alpha\/activating transcription factor 4 pathway. Circulation research \n                           113, 1253\u20131264, doi:10.1161\/CIRCRESAHA.113.301787 (2013).","journal-title":"Circulation research"},{"key":"2339_CR23","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.tox.2013.11.007","volume":"315","author":"MH Lin","year":"2014","unstructured":"Lin, M. H. et al. Lipid peroxidation end product 4-hydroxy-trans-2-nonenal triggers unfolded protein response and heme oxygenase-1 expression in PC12 cells: Roles of ROS and MAPK pathways. Toxicology \n                           315, 24\u201337, doi:10.1016\/j.tox.2013.11.007 (2014).","journal-title":"Toxicology"},{"key":"2339_CR24","doi-asserted-by":"publisher","first-page":"4843","DOI":"10.1242\/jcs.131300","volume":"126","author":"BR Webster","year":"2013","unstructured":"Webster, B. R. et al. Restricted mitochondrial protein acetylation initiates mitochondrial autophagy. Journal of cell science \n                           126, 4843\u20134849, doi:10.1242\/jcs.131300 (2013).","journal-title":"Journal of cell science"},{"key":"2339_CR25","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1161\/CIRCULATIONAHA.109.917914","volume":"122","author":"HY Fu","year":"2010","unstructured":"Fu, H. Y. et al. Ablation of C\/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. Circulation \n                           122, 361\u2013369, doi:10.1161\/CIRCULATIONAHA.109.917914 (2010).","journal-title":"Circulation"},{"key":"2339_CR26","doi-asserted-by":"publisher","first-page":"e170","DOI":"10.1038\/cddis.2011.52","volume":"2","author":"MP Lim","year":"2011","unstructured":"Lim, M. P., Devi, L. A. & Rozenfeld, R. Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. Cell death & disease \n                           2, e170, doi:10.1038\/cddis.2011.52 (2011).","journal-title":"Cell death & disease"},{"key":"2339_CR27","doi-asserted-by":"publisher","first-page":"35687","DOI":"10.1074\/jbc.M703735200","volume":"282","author":"N Ohoka","year":"2007","unstructured":"Ohoka, N., Hattori, T., Kitagawa, M., Onozaki, K. & Hayashi, H. Critical and functional regulation of CHOP (C\/EBP homologous protein) through the N-terminal portion. The Journal of biological chemistry \n                           282, 35687\u201335694, doi:10.1074\/jbc.M703735200 (2007).","journal-title":"The Journal of biological chemistry"},{"key":"2339_CR28","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1038\/cdd.2013.164","volume":"21","author":"K Jeong","year":"2014","unstructured":"Jeong, K. et al. Cyclophilin B is involved in p300-mediated degradation of CHOP in tumor cell adaptation to hypoxia. Cell death and differentiation \n                           21, 438\u2013450, doi:10.1038\/cdd.2013.164 (2014).","journal-title":"Cell death and differentiation"},{"key":"2339_CR29","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1146\/annurev-physiol-030212-183707","volume":"75","author":"J Groenendyk","year":"2013","unstructured":"Groenendyk, J., Agellon, L. B. & Michalak, M. Coping with endoplasmic reticulum stress in the cardiovascular system. Annual review of physiology \n                           75, 49\u201367, doi:10.1146\/annurev-physiol-030212-183707 (2013).","journal-title":"Annual review of physiology"},{"key":"2339_CR30","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1016\/j.yjmcc.2009.10.026","volume":"48","author":"T Minamino","year":"2010","unstructured":"Minamino, T. & Kitakaze, M. ER stress in cardiovascular disease. Journal of molecular and cellular cardiology \n                           48, 1105\u20131110, doi:10.1016\/j.yjmcc.2009.10.026 (2010).","journal-title":"Journal of molecular and cellular cardiology"},{"key":"2339_CR31","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1089\/ars.2010.3486","volume":"14","author":"G Petrovski","year":"2011","unstructured":"Petrovski, G. et al. Cardioprotection by endoplasmic reticulum stress-induced autophagy. Antioxidants & redox signaling \n                           14, 2191\u20132200, doi:10.1089\/ars.2010.3486 (2011).","journal-title":"Antioxidants & redox signaling"},{"key":"2339_CR32","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1038\/ncb1996","volume":"11","author":"CW Woo","year":"2009","unstructured":"Woo, C. W. et al. Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling. Nature cell biology \n                           11, 1473\u20131480, doi:10.1038\/ncb1996 (2009).","journal-title":"Nature cell biology"},{"key":"2339_CR33","doi-asserted-by":"publisher","first-page":"32236","DOI":"10.1074\/jbc.M112.362160","volume":"287","author":"Y Qi","year":"2012","unstructured":"Qi, Y. & Xia, P. Cellular inhibitor of apoptosis protein-1 (cIAP1) plays a critical role in beta-cell survival under endoplasmic reticulum stress: promoting ubiquitination and degradation of C\/EBP homologous protein (CHOP). The Journal of biological chemistry \n                           287, 32236\u201332245, doi:10.1074\/jbc.M112.362160 (2012).","journal-title":"The Journal of biological chemistry"},{"key":"2339_CR34","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.bbrc.2006.06.201","volume":"348","author":"Y Kuroda","year":"2006","unstructured":"Kuroda, Y., Mitsui, T., Kunishige, M. & Matsumoto, T. Parkin affects mitochondrial function and apoptosis in neuronal and myogenic cells. Biochemical and biophysical research communications \n                           348, 787\u2013793, doi:10.1016\/j.bbrc.2006.06.201 (2006).","journal-title":"Biochemical and biophysical research communications"},{"key":"2339_CR35","doi-asserted-by":"publisher","first-page":"18614","DOI":"10.1074\/jbc.M401135200","volume":"279","author":"JJ Palacino","year":"2004","unstructured":"Palacino, J. J. et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. The Journal of biological chemistry \n                           279, 18614\u201318622, doi:10.1074\/jbc.M401135200 (2004).","journal-title":"The Journal of biological chemistry"},{"key":"2339_CR36","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1161\/CIRCULATIONAHA.115.020502","volume":"133","author":"A Shirakabe","year":"2016","unstructured":"Shirakabe, A. et al. Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure. Circulation \n                           133, 1249\u20131263, doi:10.1161\/CIRCULATIONAHA.115.020502 (2016).","journal-title":"Circulation"},{"key":"2339_CR37","doi-asserted-by":"publisher","first-page":"22938","DOI":"10.1074\/jbc.M109.035774","volume":"284","author":"AK Lutz","year":"2009","unstructured":"Lutz, A. K. et al. Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. The Journal of biological chemistry \n                           284, 22938\u201322951, doi:10.1074\/jbc.M109.035774 (2009).","journal-title":"The Journal of biological chemistry"},{"key":"2339_CR38","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1083\/jcb.201007013","volume":"191","author":"A Tanaka","year":"2010","unstructured":"Tanaka, A. et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. The Journal of cell biology \n                           191, 1367\u20131380, doi:10.1083\/jcb.201007013 (2010).","journal-title":"The Journal of cell biology"},{"key":"2339_CR39","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.cell.2011.10.018","volume":"147","author":"X Wang","year":"2011","unstructured":"Wang, X. et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell \n                           147, 893\u2013906, doi:10.1016\/j.cell.2011.10.018 (2011).","journal-title":"Cell"},{"key":"2339_CR40","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1042\/BST20140321","volume":"43","author":"TR Caulfield","year":"2015","unstructured":"Caulfield, T. R., Fiesel, F. C. & Springer, W. Activation of the E3 ubiquitin ligase Parkin. Biochem Soc Trans \n                           43, 269\u2013274, doi:10.1042\/BST20140321 (2015).","journal-title":"Biochem Soc Trans"},{"key":"2339_CR41","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/nature13392","volume":"510","author":"F Koyano","year":"2014","unstructured":"Koyano, F. et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature \n                           510, 162\u2013166, doi:10.1038\/nature13392 (2014).","journal-title":"Nature"},{"key":"2339_CR42","doi-asserted-by":"publisher","first-page":"12842","DOI":"10.1074\/jbc.M608243200","volume":"282","author":"E Avraham","year":"2007","unstructured":"Avraham, E., Rott, R., Liani, E., Szargel, R. & Engelender, S. Phosphorylation of Parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. The Journal of biological chemistry \n                           282, 12842\u201312850, doi:10.1074\/jbc.M608243200 (2007).","journal-title":"The Journal of biological chemistry"},{"key":"2339_CR43","doi-asserted-by":"publisher","first-page":"16691","DOI":"10.1073\/pnas.1006083107","volume":"107","author":"HS Ko","year":"2010","unstructured":"Ko, H. S. et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin\u2019s ubiquitination and protective function. Proceedings of the National Academy of Sciences of the United States of America \n                           107, 16691\u201316696, doi:10.1073\/pnas.1006083107 (2010).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"2339_CR44","doi-asserted-by":"publisher","first-page":"10810","DOI":"10.1073\/pnas.0404161101","volume":"101","author":"D Yao","year":"2004","unstructured":"Yao, D. et al. Nitrosative stress linked to sporadic Parkinson\u2019s disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proceedings of the National Academy of Sciences of the United States of America \n                           101, 10810\u201310814, doi:10.1073\/pnas.0404161101 (2004).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"2339_CR45","doi-asserted-by":"publisher","first-page":"239854","DOI":"10.1155\/2013\/239854","volume":"2013","author":"T Omura","year":"2013","unstructured":"Omura, T., Kaneko, M., Okuma, Y., Matsubara, K. & Nomura, Y. Endoplasmic reticulum stress and Parkinson\u2019s disease: the role of HRD1 in averting apoptosis in neurodegenerative disease. Oxidative medicine and cellular longevity \n                           2013, 239854\u20137, doi:10.1155\/2013\/239854 (2013).","journal-title":"Oxidative medicine and cellular longevity"},{"key":"2339_CR46","doi-asserted-by":"publisher","first-page":"H823","DOI":"10.1152\/ajpheart.00986.2003","volume":"286","author":"SM White","year":"2004","unstructured":"White, S. M., Constantin, P. E. & Claycomb, W. C. Cardiac physiology at the cellular level: use of cultured HL-1 cardiomyocytes for studies of cardiac muscle cell structure and function. American journal of physiology. Heart and circulatory physiology \n                           286, H823\u2013829, doi:10.1152\/ajpheart.00986.2003 (2004).","journal-title":"American journal of physiology. Heart and circulatory physiology"},{"key":"2339_CR47","doi-asserted-by":"publisher","first-page":"3701","DOI":"10.1172\/JCI44736","volume":"121","author":"KY Kim","year":"2011","unstructured":"Kim, K. Y. et al. Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. The Journal of clinical investigation \n                           121, 3701\u20133712, doi:10.1172\/JCI44736 (2011).","journal-title":"The Journal of clinical investigation"},{"key":"2339_CR48","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/nbt.2647","volume":"31","author":"PD Hsu","year":"2013","unstructured":"Hsu, P. D. et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nature biotechnology \n                           31, 827\u2013832, doi:10.1038\/nbt.2647 (2013).","journal-title":"Nature biotechnology"},{"key":"2339_CR49","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1038\/nprot.2013.143","volume":"8","author":"FA Ran","year":"2013","unstructured":"Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nature protocols \n                           8, 2281\u20132308, doi:10.1038\/nprot.2013.143 (2013).","journal-title":"Nature protocols"},{"key":"2339_CR50","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/nbt.2800","volume":"32","author":"H Koike-Yusa","year":"2014","unstructured":"Koike-Yusa, H., Li, Y., Tan, E. P., Velasco-Herrera Mdel, C. & Yusa, K. Genome-wide recessive genetic screening in mammalian cells with a lentiviral CRISPR-guide RNA library. Nature biotechnology \n                           32, 267\u2013273, doi:10.1038\/nbt.2800 (2014).","journal-title":"Nature biotechnology"},{"key":"2339_CR51","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.yjmcc.2015.05.022","volume":"85","author":"KM Holmstrom","year":"2015","unstructured":"Holmstrom, K. M. et al. Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter. Journal of molecular and cellular cardiology \n                           85, 178\u2013182, doi:10.1016\/j.yjmcc.2015.05.022 (2015).","journal-title":"Journal of molecular and cellular cardiology"},{"key":"2339_CR52","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/nmeth.1593","volume":"8","author":"G Chen","year":"2011","unstructured":"Chen, G. et al. Chemically defined conditions for human iPSC derivation and culture. Nature methods \n                           8, 424\u2013429, doi:10.1038\/nmeth.1593 (2011).","journal-title":"Nature methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02339-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02339-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02339-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T04:25:50Z","timestamp":1671769550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-02339-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,18]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["2339"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-02339-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,18]]},"assertion":[{"value":"21 October 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2093"}}