NF-κB regulates protein quality control after heat stress through modulation of the BAG3-HspB8 complex.
We previously found that the NF-κB transcription factor is activated during the recovery period after heat shock; moreover, we demonstrated that NF-κB is essential for cell survival after heat shock by activating autophagy, a mechanism that probably helps the cell to cope with hyperthermic stress through clearance of damaged proteins. In this study, we analyze the involvement of NF-κB in basal and heat-stress-induced protein quality control, by comparing the level of multiubiquitylated and/or aggregated proteins, and proteasome and autophagic activity in NF-κB-competent and NF-κB-incompetent cells. We show that NF-κB has only a minor role in basal protein quality control, where it modulates autophagosome maturation. By contrast, NF-κB is shown to be a key player in protein quality control after hyperthermia. Indeed, NF-κB-incompetent cells show highly increased levels of multiubiquitylated and/or aggregated proteins and aggresome clearance defects; a phenotype that disappears when NF-κB activity is restored to normal. We demonstrate that during heat shock recovery NF-κB activates selective removal of misfolded or aggregated proteins--a process also called 'aggrephagy'--by controlling the expression of BAG3 and HSPB8 and by modulating the level of the BAG3-HspB8 complex. Thus NF-κB-mediated increase in the level of the BAG3-HspB8 complex leads to upregulation of aggrephagy and clearance of irreversibly damaged proteins and might increase cell survival in conditions of hyperthermia.
Université de Lyon, Lyon, F-69361,  France.
Mathieu
M
Nivon
Michel
M
Abou-Samra
Emma
E
Richet
Boris
B
Guyot
André-Patrick
AP
Arrigo
Carole
C
Kretz-Remy
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response / Q000502:physiology*; D006801:Humans; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; D017346:Protein Serine-Threonine Kinases