title: Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes.
abstract: Autophagy is a highly coordinated process that is controlled at several levels including transcriptional regulation. Here, we identify the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) as a regulator of autophagy gene expression and its relevance in a mouse model of Alzheimer disease (AD) that reproduces impaired APP (amyloid β precursor protein) and human (Hs)MAPT/TAU processing, clearance and aggregation. We screened the chromatin immunoprecipitation database ENCODE for 2 proteins, MAFK and BACH1, that bind the NFE2L2-regulated enhancer antioxidant response element (ARE). Using a script generated from the JASPAR's consensus ARE sequence, we identified 27 putative AREs in 16 autophagy-related genes. Twelve of these sequences were validated as NFE2L2 regulated AREs in 9 autophagy genes by additional ChIP assays and quantitative RT-PCR on human and mouse cells after NFE2L2 activation with sulforaphane. Mouse embryo fibroblasts of nfe2l2-knockout mice exhibited reduced expression of autophagy genes, which was rescued by an NFE2L2 expressing lentivirus, and impaired autophagy flux when exposed to hydrogen peroxide. NFE2L2-deficient mice co-expressing HsAPPV717Iand HsMAPTP301L, exhibited more intracellular aggregates of these proteins and reduced neuronal levels of SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5 and GABARAPL1. Also, colocalization of HsAPPV717Iand HsMAPTP301Lwith the NFE2L2-regulated autophagy marker SQSTM1/p62 was reduced in the absence of NFE2L2. In AD patients, neurons expressing high levels of APP or MAPT also expressed SQSTM1/p62 and nuclear NFE2L2, suggesting their attempt to degrade intraneuronal aggregates through autophagy. This study shows that NFE2L2 modulates autophagy gene expression and suggests a new strategy to combat proteinopathies.
authors.affiliation: a Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , Madrid , Spain.|b Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pajares
authors.affiliation: a Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , Madrid , Spain.|b Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain.|c Present address: School of Biochemistry, University of Bristol, Medical Sciences Building, University Walk , Bristol , UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Jiménez-Moreno
authors.affiliation: a Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , Madrid , Spain.|b Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain.
authors.forename: Ángel J
authors.initials: ÁJ
authors.lastname: García-Yagüe
authors.affiliation: a Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , Madrid , Spain.|b Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Escoll
authors.affiliation: b Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain.|d Neurodegeneration Group, Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, Consejo Superior de Investigaciones Científicas , Madrid , Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: de Ceballos
authors.affiliation: e Experimental Genetics Group-LEGTEGG, Department of Human Genetics, KU Leuven , Leuven , Belgium.
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.affiliation: f Department of Neuropathology and Tissue Bank , Unidad de Investigación Proyecto Alzheimer, Fundación CIEN, Instituto de Salud Carlos III , Madrid , Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.affiliation: g Department of Medical Biochemistry , Tohoku University Graduate School of Medicine , Aoba-ku , Sendai , Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: a Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , Madrid , Spain.|b Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rojo
authors.affiliation: a Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz) and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid , Madrid , Spain.|b Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII , Madrid , Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2
keywords: Alzheimer disease; Tau; amyloid precursor protein; neurodegenerative diseases; neuroprotection; oxidative stress; proteostasis