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Mol Biol Cell. 2016 Jun 1;27(11):1712-27. doi: 10.1091/mbc.E15-12-0835. Epub 2016 Apr 13.

NFκB is a central regulator of protein quality control in response to protein aggregation stresses via autophagy modulation.

Author information

1
Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France.
2
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, 70086 Santiago, Chile Center for Geroscience, Brain Health and Metabolism, 70086 Santiago, Chile.
3
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
4
Université de Lyon, 69622 Lyon, France CNRS, UMR 5310, INSERM U1217, Institut NeuroMyoGène, Université Lyon 1, 69100 Villeurbanne, France carole.kretz@univ-lyon1.fr.

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.

PMID:
27075172
PMCID:
PMC4884063
DOI:
10.1091/mbc.E15-12-0835
[Indexed for MEDLINE]
Free PMC Article

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