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

Mathieu Nivon, Loïc Fort, Pascale Muller, Emma Richet, Stéphanie Simon, Baptiste Guey, Maëlenn Fournier, André Patrick Arrigo, Claudio Hetz, Julie D. Atkin, Carole Kretz-Remy

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages1712-1727
Number of pages16
JournalMolecular Biology of the Cell
Volume27
Issue number11
DOIs
Publication statusPublished - 1 Jun 2016

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Autophagy
Heat-Shock Proteins
Quality Control
Proteins
Poisons
Transcription Factors
Up-Regulation
Protein Aggregates
Pharmacology
Amino Acids
Mutation
Amyotrophic lateral sclerosis 1
Myofibrillar Myopathy

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

Nivon, Mathieu ; Fort, Loïc ; Muller, Pascale ; Richet, Emma ; Simon, Stéphanie ; Guey, Baptiste ; Fournier, Maëlenn ; Arrigo, André Patrick ; Hetz, Claudio ; Atkin, Julie D. ; Kretz-Remy, Carole. / NFκB is a central regulator of protein quality control in response to protein aggregation stresses via autophagy modulation. In: Molecular Biology of the Cell. 2016 ; Vol. 27, No. 11. pp. 1712-1727.
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Nivon, M, Fort, L, Muller, P, Richet, E, Simon, S, Guey, B, Fournier, M, Arrigo, AP, Hetz, C, Atkin, JD & Kretz-Remy, C 2016, 'NFκB is a central regulator of protein quality control in response to protein aggregation stresses via autophagy modulation', Molecular Biology of the Cell, vol. 27, no. 11, pp. 1712-1727. https://doi.org/10.1091/mbc.E15-12-0835

NFκB is a central regulator of protein quality control in response to protein aggregation stresses via autophagy modulation. / Nivon, Mathieu; Fort, Loïc; Muller, Pascale; Richet, Emma; Simon, Stéphanie; Guey, Baptiste; Fournier, Maëlenn; Arrigo, André Patrick; Hetz, Claudio; Atkin, Julie D.; Kretz-Remy, Carole.

In: Molecular Biology of the Cell, Vol. 27, No. 11, 01.06.2016, p. 1712-1727.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Guey, Baptiste

AU - Fournier, Maëlenn

AU - Arrigo, André Patrick

AU - Hetz, Claudio

AU - Atkin, Julie D.

AU - Kretz-Remy, Carole

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