Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

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dc.contributor.author Pajares, Marta
dc.contributor.author Rojo, Ana I.
dc.contributor.author Arias, Esperanza
dc.contributor.author Díaz-Carretero, Antonio
dc.contributor.author Cuervo, Ana María
dc.contributor.author Cuadrado, Antonio
dc.contributor.other UAM. Departamento de Bioquímica es_ES
dc.contributor.other Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM) es_ES
dc.contributor.other Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ) es_ES
dc.date.accessioned 2018-10-31T18:00:02Z
dc.date.available 2018-10-31T18:00:02Z
dc.date.issued 2018-08-03
dc.identifier.citation Autophagy 14.8 (2018): 1310–1322 en_US
dc.identifier.issn 1554-8627 (print) es_ES
dc.identifier.issn 1554-8635 (online) es_ES
dc.identifier.uri http://hdl.handle.net/10486/685421
dc.description.abstract Chaperone-mediated autophagy (CMA) is a selective degradative process for cytosolic proteins that contributes to the maintenance of proteostasis. The signaling mechanisms that control CMA are not fully understood but might involve response to stress conditions including oxidative stress. Considering the role of CMA in redoxtasis and proteostasis, we sought to determine if the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) has an impact on CMA modulation. In this work, we identified and validated 2 NFE2L2 binding sequences in the LAMP2 gene and demonstrated in several human and mouse cell types that NFE2L2 deficiency and overexpression was linked to reduced and increased LAMP2A levels, respectively. Accordingly, lysosomal LAMP2A levels were drastically reduced in nfe2l2-knockout hepatocytes, which also displayed a marked decrease in CMA activity. Oxidant challenge with paraquat or hydrogen peroxide, or pharmacological activation of NFE2L2 with sulforaphane or dimethyl fumarate also increased LAMP2A levels and CMA activity. Overall, our study identifies for the first time basal and inducible regulation of LAMP2A, and consequently CMA activity, by NFE2L2. Abbreviations: ACTB: actin, beta, ARE: antioxidant response element; ATG5: autophagy related 5; BACH1: BTB domain and CNC homolog 1; ChIP: chromatin immunoprecipitation; CMA: chaperone-mediated autophagy; DHE: dihydroethidium; DMF: dimethyl fumarate; ENCODE: Encyclopedia of DNA elements at the University of California, Santa Cruz; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA: glucosylceramidase beta; GFP: green fluorescent protein; HMOX1: heme oxygenase 1; H2O2: hydrogen peroxide; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; LAMP1: lysosomal associated membrane protein 1; MAFF: MAF bZIP transcription factor F; MAFK: MAF bZIP transcription factor K; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PQ: paraquat; PI: protease inhibitors; qRT-PCR: quantitative real-time polymerase chain reaction; RNASE: ribonuclease A family member; SFN: sulforaphane; SQSTM1/p62: sequestosome 1; TBP: TATA-box binding protein en_US
dc.description.sponsorship This paper was funded by the Spanish Ministry of Economy and Competitiveness under the grant SAF2016-76520-R and by grants from the National Institute of Health/National Institute on Aging P01 AG031782. M.P. is recipient of a FPU fellowship of Autonomous University of Madrid. E.A. was supported by NIH/NIA AG038072 P&F en_US
dc.format.extent 13 pag. es_ES
dc.format.mimetype application/pdf en
dc.language.iso eng en
dc.publisher Informa UK Limited, trading as Taylor & Francis Group en_US
dc.relation.ispartof Autophagy en_US
dc.rights © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. en_US
dc.subject.other LAMP2A en_US
dc.subject.other NRF2 en_US
dc.subject.other Proteostasis en_US
dc.title Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.relation.publisherversion https://doi.org/10.1080/15548627.2018.1474992 es_ES
dc.identifier.doi 10.1080/15548627.2018.1474992 es_ES
dc.identifier.publicationfirstpage 1310 es_ES
dc.identifier.publicationissue 8 es_ES
dc.identifier.publicationlastpage 1322 es_ES
dc.identifier.publicationvolume 14 es_ES
dc.relation.projectID Gobierno de España. SAF2016-76520-R es_ES
dc.type.version info:eu-repo/semantics/publishedVersion en
dc.rights.cc Reconocimiento – NoComercial – SinObraDerivada es_ES
dc.rights.accessRights openAccess en


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