PMID- 29950142 OWN - NLM STAT- MEDLINE DCOM- 20191011 LR - 20210202 IS - 1554-8635 (Electronic) IS - 1554-8627 (Print) IS - 1554-8627 (Linking) VI - 14 IP - 8 DP - 2018 TI - Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A. PG - 1310-1322 LID - 10.1080/15548627.2018.1474992 [doi] AB - 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; H(2)O(2): 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. FAU - Pajares, Marta AU - Pajares M AD - a Instituto de Investigaciones Biomedicas "Alberto Sols" UAM-CSIC, Instituto de Investigacion Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine , Autonomous University of Madrid , Madrid , Spain. AD - b Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain. FAU - Rojo, Ana I AU - Rojo AI AD - a Instituto de Investigaciones Biomedicas "Alberto Sols" UAM-CSIC, Instituto de Investigacion Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine , Autonomous University of Madrid , Madrid , Spain. AD - b Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain. FAU - Arias, Esperanza AU - Arias E AD - c Department of Developmental and Molecular Biology and Institute for Aging Studies , Albert Einstein College of Medicine , Bronx , NY , USA. FAU - Diaz-Carretero, Antonio AU - Diaz-Carretero A AD - c Department of Developmental and Molecular Biology and Institute for Aging Studies , Albert Einstein College of Medicine , Bronx , NY , USA. FAU - Cuervo, Ana Maria AU - Cuervo AM AD - c Department of Developmental and Molecular Biology and Institute for Aging Studies , Albert Einstein College of Medicine , Bronx , NY , USA. FAU - Cuadrado, Antonio AU - Cuadrado A AD - a Instituto de Investigaciones Biomedicas "Alberto Sols" UAM-CSIC, Instituto de Investigacion Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine , Autonomous University of Madrid , Madrid , Spain. AD - b Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain. LA - eng GR - P30 AG038072/AG/NIA NIH HHS/United States GR - R37 AG021904/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180726 PL - United States TA - Autophagy JT - Autophagy JID - 101265188 RN - 0 (Lysosomal-Associated Membrane Protein 2) RN - 0 (Molecular Chaperones) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Oxidants) RN - PLG39H7695 (Paraquat) SB - IM MH - A549 Cells MH - Animals MH - Antioxidant Response Elements/genetics MH - *Autophagy/drug effects MH - HEK293 Cells MH - Humans MH - Lysosomal-Associated Membrane Protein 2/genetics/*metabolism MH - Mice, Knockout MH - Molecular Chaperones/*metabolism MH - NF-E2-Related Factor 2/*metabolism MH - Oxidants/toxicity MH - Paraquat/toxicity MH - Protein Binding/drug effects PMC - PMC6103698 OTO - NOTNLM OT - LAMP2A OT - NRF2 OT - proteostasis EDAT- 2018/06/29 06:00 MHDA- 2019/10/12 06:00 PMCR- 2018/07/26 CRDT- 2018/06/29 06:00 PHST- 2018/06/29 06:00 [pubmed] PHST- 2019/10/12 06:00 [medline] PHST- 2018/06/29 06:00 [entrez] PHST- 2018/07/26 00:00 [pmc-release] AID - 1474992 [pii] AID - 10.1080/15548627.2018.1474992 [doi] PST - ppublish SO - Autophagy. 2018;14(8):1310-1322. doi: 10.1080/15548627.2018.1474992. Epub 2018 Jul 26.