{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T20:16:26Z","timestamp":1774728986406,"version":"3.50.1"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T00:00:00Z","timestamp":1698105600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["NRF-2021R1A2C1005469"],"award-info":[{"award-number":["NRF-2021R1A2C1005469"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a common neurodegenerative disease (NDD) characterized by the loss of dopaminergic neurons in the substantia nigra. Similar to other NDDs, the buildup of toxic protein aggregates in PD leads to progressive neuronal loss, culminating in neurodegeneration. Accumulating evidence indicates that alterations in subcellular organelles, particularly the endoplasmic reticulum (ER), are critically involved in pathological neurodegenerative events in NDDs, including PD. Mutations in the F-box only protein 7 (<jats:italic>FBXO7<\/jats:italic> or <jats:italic>PARK15<\/jats:italic>) gene have been found to cause early onset autosomal recessive familiar PD. FBXO7 functions as an adaptor protein in the Skp1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complex, which promotes substrate ubiquitination. Although FBXO7 is involved in the ubiquitination of various target proteins, little is known about the upstream regulatory mechanism of FBXO7 and\/or its modulator(s). Ubiquitin specific protease 7 (USP7) is a deubiquitinating enzyme that regulates the balance between protein synthesis and degradation by removing ubiquitin from target substrates. The role of USP7 in various types of cancer is well-established; however, its role in NDDs has not been elucidated to date. In this study, we identified that USP7 acts as a novel regulator of FBXO7, positively regulating the stability of FBXO7 through Lys48-linked deubiquitination. Moreover, USP7 was found to mitigate ER stress-induced cytotoxicity and apoptosis by preventing the proteasomal degradation of FBXO7. Taken together, our study suggests that the functional relationship between FBXO7 and USP7 may play a crucial role in ER stress-induced apoptosis and the pathogenesis of PD.<\/jats:p>","DOI":"10.1371\/journal.pone.0290371","type":"journal-article","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T17:28:53Z","timestamp":1698168533000},"page":"e0290371","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["USP7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of FBXO7"],"prefix":"10.1371","volume":"18","author":[{"given":"Su Hyoun","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4658-3849","authenticated-orcid":true,"given":"Kwang Chul","family":"Chung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,10,24]]},"reference":[{"issue":"363","key":"pone.0290371.ref001","first-page":"1783","article-title":"Parkinson\u2019s disease","volume":"29","author":"JG Samii A Nutt","year":"2004","journal-title":"Lancet"},{"issue":"3","key":"pone.0290371.ref002","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s00401-012-1013-5","article-title":"The genetics and neuropathology of Parkinson\u2019s disease","volume":"124","author":"H Houlden","year":"2012","journal-title":"Acta. Neuropathol"},{"key":"pone.0290371.ref003","doi-asserted-by":"crossref","first-page":"612476","DOI":"10.3389\/fcell.2021.612476","article-title":"PARK genes link mitochondrial dysfunction and alpha-synuclein pathology in sporadic Parkinson\u2019s disease","volume":"9","author":"W Li","year":"2021","journal-title":"Front. Cell. Dev. Biol"},{"issue":"10","key":"pone.0290371.ref004","doi-asserted-by":"crossref","first-page":"130131","DOI":"10.1098\/rsob.130131","article-title":"Beyond ubiquitination: The atypical functions of Fbxo7 and other F-box proteins","volume":"3","author":"D Nelson","year":"2013","journal-title":"Open Biol"},{"issue":"31","key":"pone.0290371.ref005","doi-asserted-by":"crossref","first-page":"32592","DOI":"10.1074\/jbc.M404950200","article-title":"Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-phosphorylated hepatoma up-regulated protein (HURP) proteolysis by a proline-rich region","volume":"279","author":"JM Hsu","year":"2004","journal-title":"J. Biol. Chem"},{"issue":"4","key":"pone.0290371.ref006","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.bbrc.2006.02.061","article-title":"The F-box protein Fbxo7 interacts with human inhibitor of apoptosis protein cIAP1 and promotes cIAP1 ubiquitination","volume":"342","author":"YF Chang","year":"2006","journal-title":"Biochem. Biophys. Res. Commun"},{"issue":"1","key":"pone.0290371.ref007","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s00018-014-1665-5","article-title":"The F-box protein FBXO7 positively regulates bone morphogenetic protein-mediated signaling through Lys-63-specific ubiquitination of neurotrophin receptor-interacting MAGE (NRAGE)","volume":"72","author":"J Kang","year":"2015","journal-title":"Cell. Mol. Life Sci"},{"issue":"18","key":"pone.0290371.ref008","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.15252\/embj.201593585","article-title":"Loss of FBXO7 (PAKR15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice","volume":"35","author":"S Vingill","year":"2016","journal-title":"EMBO J"},{"issue":"20","key":"pone.0290371.ref009","doi-asserted-by":"crossref","first-page":"3563","DOI":"10.1042\/BCJ20160387","article-title":"Gsk3\u03b2 and Tomm20 are substrates of the SCFFbxo7\/PARK15 ubiquitin ligase associated with Parkinson\u2019s disease","volume":"473","author":"FR Teixeira","year":"2016","journal-title":"Biochem. J"},{"issue":"3","key":"pone.0290371.ref010","doi-asserted-by":"crossref","first-page":"102909","DOI":"10.1016\/j.jbc.2023.102909","article-title":"E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation of SIRT7 and promotes cell death in response to hydrogen peroxide","volume":"299","author":"SH Lee","year":"2023","journal-title":"J. Biol. Chem"},{"issue":"6","key":"pone.0290371.ref011","doi-asserted-by":"crossref","first-page":"101426","DOI":"10.1016\/j.jbc.2021.101426","article-title":"FBXO7 triggers caspase 8-mediated proteolysis of the transcription factor FOXO4 and exacerbates neuronal cytotoxicity","volume":"297","author":"SH Lee","year":"2021","journal-title":"J. Biol. Chem"},{"issue":"6","key":"pone.0290371.ref012","first-page":"4774","article-title":"Role of endoplasmic reticulum stress in depression","volume":"20","author":"J Mao","year":"2019","journal-title":"Mol. Med. Rep"},{"issue":"3","key":"pone.0290371.ref013","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ncb0311-184","article-title":"Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress","volume":"13","author":"I Tabas","year":"2011","journal-title":"Nat. Cell Biol"},{"issue":"8","key":"pone.0290371.ref014","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1016\/j.molcel.2022.03.025","article-title":"Reshaping endoplasmic reticulum quality control through the unfolded protein response","volume":"82","author":"RL Wiseman","year":"2022","journal-title":"Mol. Cell"},{"issue":"7","key":"pone.0290371.ref015","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1016\/j.ajpath.2015.03.009","article-title":"Multiple mechanisms of unfolded protein response-induced cell death","volume":"185","author":"N Hiramatsu","year":"2015","journal-title":"Am. J. Pathol"},{"issue":"4","key":"pone.0290371.ref016","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.3390\/ijms22041526","article-title":"The roles of the ubiquitin-proteasome system in the endoplasmic reticulum stress pathway","volume":"22","author":"J Qu","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"23","key":"pone.0290371.ref017","doi-asserted-by":"crossref","first-page":"15186","DOI":"10.3390\/ijms232315186","article-title":"Endoplasmic reticulum stress signaling and neuronal cell death","volume":"23","author":"A Merighi","year":"2022","journal-title":"Int. J. Mol. Sci"},{"issue":"12","key":"pone.0290371.ref018","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1016\/j.bbamcr.2013.06.028","article-title":"ER stress-induced cell death mechanisms","volume":"1833","author":"R Sano","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"issue":"11","key":"pone.0290371.ref019","doi-asserted-by":"crossref","first-page":"5894","DOI":"10.3390\/ijms23115894","article-title":"The Common cellular events in the neurodegenerative diseases and the associated role of endoplasmic reticulum stress","volume":"23","author":"S Kim","year":"2022","journal-title":"Int. J. Mol. Sci"},{"issue":"2","key":"pone.0290371.ref020","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.drudis.2020.10.028","article-title":"The emerging nature of ubiquitin-specific protease 7 (USP7): a new target in cancer therapy","volume":"26","author":"L Nininahazwe","year":"2021","journal-title":"Drug Discov. Today"},{"key":"pone.0290371.ref021","doi-asserted-by":"crossref","first-page":"105273","DOI":"10.1016\/j.bioorg.2021.105273","article-title":"Recent advances on the intervention sites targeting USP7-MDM2-p53 in cancer therapy","volume":"116","author":"C Harakandi","year":"2021","journal-title":"Bioorg. Chem"},{"issue":"1","key":"pone.0290371.ref022","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.gendis.2020.10.004","article-title":"The USP7 protein interaction network and its roles in tumorigenesis","volume":"9","author":"A Al-Eidan","year":"2020","journal-title":"Genes Dis"},{"issue":"32","key":"pone.0290371.ref023","doi-asserted-by":"crossref","first-page":"13296","DOI":"10.1074\/jbc.M117.780130","article-title":"Ubiquitin-specific peptidase 7 (USP7)-mediated deubiquitination of the histone deacetylase SIRT7 regulates gluconeogenesis","volume":"292","author":"L Jiang","year":"2017","journal-title":"J. Biol. Chem"},{"issue":"10","key":"pone.0290371.ref024","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/ncb1469","article-title":"FOXO4 transcriptional activity is regulated by monoubiquitination and USP7\/HAUSP","volume":"8","author":"A van der Horst","year":"2006","journal-title":"Nat. Cell Biol"},{"issue":"1","key":"pone.0290371.ref025","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.bbrc.2016.01.021","article-title":"Small-molecule inhibitors of USP7 induce apoptosis through oxidative and endoplasmic reticulum stress in cancer cells","volume":"470","author":"G Lee","year":"2016","journal-title":"Biochem. Biophys. Res. Commun"},{"issue":"9","key":"pone.0290371.ref026","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1038\/nn.3489","article-title":"The Parkinson\u2019s disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy","volume":"16","author":"VS Burchell","year":"2013","journal-title":"Nat. Neurosci"},{"key":"pone.0290371.ref027","doi-asserted-by":"crossref","first-page":"691881","DOI":"10.3389\/fnagi.2021.691881","article-title":"The cross-links of endoplasmic reticulum stress, autophagy, and neurodegeneration in Parkinson\u2019s disease","volume":"13","author":"H Ren","year":"2021","journal-title":"Front. Aging Neurosci"},{"issue":"46","key":"pone.0290371.ref028","doi-asserted-by":"crossref","first-page":"35661","DOI":"10.1074\/jbc.C000447200","article-title":"Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity","volume":"275","author":"Y Imai","year":"2000","journal-title":"J. Biol. Chem"},{"issue":"5","key":"pone.0290371.ref029","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/cdd.2010.142","article-title":"Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress","volume":"18","author":"L Bouman","year":"2011","journal-title":"Cell Death Differ"},{"issue":"10","key":"pone.0290371.ref030","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.4161\/auto.32136","article-title":"Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy","volume":"10","author":"X Zhang","year":"2014","journal-title":"Autophagy"},{"key":"pone.0290371.ref031","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1146\/annurev-biochem-061516-044908","article-title":"Proteasomal and autophagic degradation systems","volume":"86","author":"I. Dikic","year":"2017","journal-title":"Annu. Rev. Biochem"},{"issue":"5","key":"pone.0290371.ref032","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/jb\/mvu016","article-title":"Roles of mitochondrial ubiquitin ligase MITOL\/MARCH5 in mitochondrial dynamics and disease","volume":"155","author":"S Nagashima","year":"2014","journal-title":"J. Biochem"},{"issue":"15","key":"pone.0290371.ref033","doi-asserted-by":"crossref","first-page":"e100999","DOI":"10.15252\/embj.2018100999","article-title":"MITOL prevents ER stress-induced apoptosis by IRE1alpha ubiquitylation at ER-mitochondria contact sites","volume":"38","author":"K Takeda","year":"2019","journal-title":"EMBO J"},{"issue":"11","key":"pone.0290371.ref034","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1016\/j.cellsig.2013.07.016","article-title":"A novel RING finger E3 ligase RNF186 regulate ER stress-mediated apoptosis through interaction with BNip1","volume":"25","author":"P Wang","year":"2013","journal-title":"Cell signal"},{"key":"pone.0290371.ref035","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.cellsig.2018.09.008","article-title":"RNF186 impairs insulin sensitivity by inducing ER stress in mouse primary hepatocytes","volume":"52","author":"X Tong","year":"2018","journal-title":"Cell. Signal"},{"key":"pone.0290371.ref036","doi-asserted-by":"crossref","first-page":"e01369","DOI":"10.7554\/eLife.01369","article-title":"USP13 antagonizes gp78 to maintain functionality of a chaperone in ER-associated degradation","volume":"3","author":"Y Liu","year":"2014","journal-title":"eLife"},{"issue":"17","key":"pone.0290371.ref037","doi-asserted-by":"crossref","first-page":"4878","DOI":"10.7150\/thno.36254","article-title":"Repurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy","volume":"9","author":"Z Zhang","year":"2019","journal-title":"Theranostics"},{"issue":"6","key":"pone.0290371.ref038","doi-asserted-by":"crossref","first-page":"299","DOI":"10.5483\/BMBRep.2017.50.6.056","article-title":"Emerging role of mitophagy in human diseases and physiology","volume":"50","author":"JH Um","year":"2017","journal-title":"BMB Rep"},{"issue":"21","key":"pone.0290371.ref039","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.15252\/embj.201489729","article-title":"USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin","volume":"33","author":"TM Durcan","year":"2014","journal-title":"EMBO J"},{"issue":"7505","key":"pone.0290371.ref040","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/nature13418","article-title":"The mitochondrial deubiquitinase USP30 opposes Parkin-mediated mitophagy","volume":"510","author":"B Bingol","year":"2014","journal-title":"Nature"},{"issue":"19","key":"pone.0290371.ref041","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1093\/hmg\/ddu244","article-title":"The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy","volume":"23","author":"T Cornelissen","year":"2014","journal-title":"Hum. Mol. Genet"},{"issue":"4","key":"pone.0290371.ref042","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1080\/15548627.2019.1656957","article-title":"USP33 deubiquitinates PRKN\/Parkin and antagonizes its role in mitophagy","volume":"16","author":"K Niu","year":"2020","journal-title":"Autophagy"},{"issue":"11","key":"pone.0290371.ref043","doi-asserted-by":"crossref","first-page":"e131834","DOI":"10.1172\/jci.insight.131834","article-title":"Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1","volume":"5","author":"Y Liu","year":"2020","journal-title":"JCI Insight"},{"issue":"22","key":"pone.0290371.ref044","doi-asserted-by":"crossref","first-page":"6314","DOI":"10.1093\/hmg\/ddv340","article-title":"F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy","volume":"24","author":"ZD Zhou","year":"2015","journal-title":"Hum. Mol. Genet"},{"issue":"1","key":"pone.0290371.ref045","doi-asserted-by":"crossref","first-page":"77","DOI":"10.18632\/aging.202236","article-title":"Fbxo7 and Pink1 play a reciprocal role in regulating their protein levels","volume":"13","author":"T Huang","year":"2020","journal-title":"Aging (Albany NY)"}],"updated-by":[{"DOI":"10.1371\/journal.pone.0297970","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:00:00Z","timestamp":1706054400000}}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0290371","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T18:52:41Z","timestamp":1705517561000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0290371"}},"subtitle":[],"editor":[{"given":"Dipankar","family":"Ray","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,10,24]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0290371","relation":{"correction":[{"id-type":"doi","id":"10.1371\/journal.pone.0297970","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,24]]}}}