Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 27, Issue 11, Pages 1712-1727Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E15-12-0835
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Funding
- Ligue contre le Cancer, comite du Rhone
- Ligue contre le Cancer, comite de Savoie
- Bonus Qualite Recherche from Universite Claude Bernard Lyon 1
- Centre National de la Recherche Scientifique
- Millennium Institute [P09-015-F]
- FONDAP Program [15150012]
- French Department of research
- Fondation pour la Recherche Medicale
- Association Francaise contre les Myopathies/Telethon
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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 NF kappa B 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 NF kappa B triggers the up-regulation of BAG3 and HspB8 expression, two activators of selective autophagy, which relocalize to protein aggregates. Then NF kappa B-dependent autophagy allows the clearance of protein aggregates. Thus NF kappa B 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.
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