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RESEARCH PRODUCT

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

Elisabeth SehnChristian BehlChristof HiebelFranz H. GrusVanessa FelzenUwe WolfrumCaroline ManicamNatarajan PerumalDebapriya ChakrabortyElisabeth Stürner

subject

0301 basic medicineClinical BiochemistryLFQ Label-free quantificationLETM Leucine zipper and EF-hand containing transmembrane proteinmedicine.disease_causeBiochemistryCHX Cycloheximide0302 clinical medicineBNIP3 Bcl-2 interacting protein 3RAPA RapamycinPIK3C3 Class III PI3‐kinasePhosphorylationlcsh:QH301-705.5Neuronslcsh:R5-920PolyUB PolyubiquitinChemistryBAG3OPA1 Optic atrophy 1TOR Serine-Threonine KinasesWIPI1 WD repeat domain phosphoinositide-interacting protein 1ATG Autophagy relatedTFEB Transcription factor EBCell biologyMitochondriasiRNA Small interfering RNADLP1 Dynamin-like protein 1LAMP1 Lysosomal‐associated membrane protein 1PURO Puromycinlcsh:Medicine (General)Protein homeostasisResearch PaperBafA1 Bafilomycin A1LAMP2 Lysosomal‐associated membrane protein 2Proteasome Endopeptidase ComplexRAB18 Member RAS oncogeneTUB TubulinLC3 Light chain 3 proteinOxidative phosphorylationBAG3CTSD Cathepsin DModels BiologicalCell Line03 medical and health sciencesDownregulation and upregulationMacroautophagymedicineAutophagyHumansAdaptationBAG1 Bcl-2-associated athanogene 1BECN1 Beclin1PI3K/AKT/mTOR pathwayAdaptor Proteins Signal TransducingTEM Transmission electron microscopyHsp70 Heat shock protein 70Organic ChemistryAutophagyAutophagosomesmTOR Mammalian target of rapamycinHsp70Oxidative Stress030104 developmental biologyProteostasislcsh:Biology (General)CV CanavanineBAG3 Bcl-2-associated athanogene 3MTT (3-(45-Dimethylthiazol-2-yl)-25-Diphenyltetrazolium Bromide)Apoptosis Regulatory ProteinsLysosomes030217 neurology & neurosurgeryOxidative stress

description

Oxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here, we report that hippocampal cells selected for full adaptation and resistance to oxidative stress induced by hydrogen peroxide (oxidative stress-resistant cells, OxSR cells) showed a massive increase in the expression of components of the cellular autophagic-lysosomal network and a significantly higher overall autophagic activity. A comparative expression analysis revealed that distinct key regulators of autophagy are upregulated in OxSR cells. The observed adaptive autophagic response was found to be independent of the upstream autophagy regulator mTOR but is accompanied by a significant upregulation of further downstream components of the canonical autophagy network such as Beclin1, WIPI1 and the transmembrane ATG9 proteins. Interestingly, the expression of the HSP70 co-chaperone BAG3, mediator of BAG3-mediated selective macroautophagy and highly relevant for the clearance of aggregated proteins in cells, was found to be increased in OxSR cells that were consequently able to effectively overcome proteotoxic stress. Overexpression of BAG3 in oxidative stress-sensitive HT22 wildtype cells partly established the vesicular phenotype and the enhanced autophagic flux seen in OxSR cells suggesting that BAG3 takes over an important part in the adaptation process. A full proteome analysis demonstrated additional changes in the expression of mitochondrial proteins, metabolic enzymes and different pathway regulators in OxSR cells as consequence of the adaptation to oxidative stress in addition to autophagy-related proteins. Taken together, this analysis revealed a wide variety of pathways and players that act as adaptive response to chronic redox stress in neuronal cells.

yearjournalcountryeditionlanguage
2019-06-01Redox Biology
10.1016/j.redox.2019.101181http://europepmc.org/articles/PMC6454062