title: NFκB is a central regulator of protein quality control in response to protein aggregation stresses via autophagy modulation.
abstract: During cell life, proteins often misfold, depending on particular mutations or environmental changes, which may lead to protein aggregates that are toxic for the cell. Such protein aggregates are the root cause of numerous diseases called "protein conformational diseases," such as myofibrillar myopathy and familial amyotrophic lateral sclerosis. To fight against aggregates, cells are equipped with protein quality control mechanisms. Here we report that NFκB transcription factor is activated by misincorporation of amino acid analogues into proteins, inhibition of proteasomal activity, expression of the R120G mutated form of HspB5 (associated with myofibrillar myopathy), or expression of the G985R and G93A mutated forms of superoxide dismutase 1 (linked to familial amyotrophic lateral sclerosis). This noncanonical stimulation of NFκB triggers the up-regulation of BAG3 and HspB8 expression, two activators of selective autophagy, which relocalize to protein aggregates. Then NFκB-dependent autophagy allows the clearance of protein aggregates. Thus NFκB appears as a central and major regulator of protein aggregate clearance by modulating autophagic activity. In this context, the pharmacological stimulation of this quality control pathway might represent a valuable strategy for therapies against protein conformational diseases.
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Nivon
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Fort
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Muller
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
authors.forename: Emma
authors.initials: E
authors.lastname: Richet
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Simon
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Guey
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
authors.forename: Maëlenn
authors.initials: M
authors.lastname: Fournier
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
authors.forename: André-Patrick
authors.initials: AP
authors.lastname: Arrigo
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, 70086 Santiago, Chile Center for Geroscience, Brain Health and Metabolism, 70086 Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
authors.affiliation: Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France carole.kretz@univ-lyon1.fr.
authors.forename: Carole
authors.initials: C
authors.lastname: Kretz-Remy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C059215:CRYAB protein, human; D016328:NF-kappa B; D038203:alpha-Crystallin B Chain; D000072105:Superoxide Dismutase-1; D017346:Protein Serine-Threonine Kinases