The accumulation of misfolded, mutant proteins is a common basis for many adult onset neurodegenerative diseases. Cells have evolved an elaborate protein quality control system, which acts to facilitate the folding or refolding of misfolded protein species by molecular chaperones or, if folding is unsuccessful, these same chaperones often target the misfolded proteins for degradation, thereby preventing protein aggregation. Intracellular degradation is primarily mediated by two proteolytic systems: the autophagy and the ubiquitin proteasomal systems. Proteotoxic stress can lead to proteasomal impairment and augmented authophagosomal capacity in order to ensure proper clearance of clients (proteasome-autophagy switch). However, neither the mechanism of sensing nor that of switching is understood. Here, we show that the ER is main sensor for proteasomal inhibition through the IRE-1alpha-Xbp-1 signalling cascade. After proteasome inhibition, BAG-3 is upregulated in a HSF-1 independent manner, but in a Xbp-1 dependent manner and is a major executor of the proteasome-autophagy switch. BAG-3 both boosts autophagy and redirects HSP70-bound proteasomal clients to autophagosomes through competitive inhibition with its family member BAG-1, that normally directs HSP70-bound clients to the proteasome, thus playing a key role in the maintenance of protein homeostasis under proteotoxic stress conditions.

SENSING AND REROUTING OF PROTEIN DEGRADATION TOWARDS AUTOPHAGY UPON PROTEASOMAL IMPAIRMENT / Boncoraglio, Alessandra; Minoia, Melania; Brunsting, Jeanette F.; Reits, Eric; Kampinga, Harm H.; Carra, Serena. - (2012), pp. 1-1.

SENSING AND REROUTING OF PROTEIN DEGRADATION TOWARDS AUTOPHAGY UPON PROTEASOMAL IMPAIRMENT

CARRA, Serena
2012

Abstract

The accumulation of misfolded, mutant proteins is a common basis for many adult onset neurodegenerative diseases. Cells have evolved an elaborate protein quality control system, which acts to facilitate the folding or refolding of misfolded protein species by molecular chaperones or, if folding is unsuccessful, these same chaperones often target the misfolded proteins for degradation, thereby preventing protein aggregation. Intracellular degradation is primarily mediated by two proteolytic systems: the autophagy and the ubiquitin proteasomal systems. Proteotoxic stress can lead to proteasomal impairment and augmented authophagosomal capacity in order to ensure proper clearance of clients (proteasome-autophagy switch). However, neither the mechanism of sensing nor that of switching is understood. Here, we show that the ER is main sensor for proteasomal inhibition through the IRE-1alpha-Xbp-1 signalling cascade. After proteasome inhibition, BAG-3 is upregulated in a HSF-1 independent manner, but in a Xbp-1 dependent manner and is a major executor of the proteasome-autophagy switch. BAG-3 both boosts autophagy and redirects HSP70-bound proteasomal clients to autophagosomes through competitive inhibition with its family member BAG-1, that normally directs HSP70-bound clients to the proteasome, thus playing a key role in the maintenance of protein homeostasis under proteotoxic stress conditions.
2012
Boncoraglio, Alessandra; Minoia, Melania; Brunsting, Jeanette F.; Reits, Eric; Kampinga, Harm H.; Carra, Serena
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1063161
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact