Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability

Am J Pathol. 2007 Aug;171(2):513-24. doi: 10.2353/ajpath.2007.070188. Epub 2007 Jul 9.

Abstract

Two major protein degradation systems exist in cells, the ubiquitin proteasome system and the autophagy machinery. Here, we investigated the functional relationship of the two systems and the underlying mechanisms. Proteasome inhibition activated autophagy, suggesting that the two are functionally coupled. Autophagy played a compensatory role as suppression of autophagy promoted the accumulation of polyubiquitinated protein aggregates. Autophagy was likely activated in response to endoplasmic reticulum stress caused by misfolded proteins during proteasome inhibition. Suppression of a major unfolded protein response pathway mediated by IRE1 by either gene deletion or RNA interference dramatically suppressed the activation of autophagy by proteasome inhibitors. Interestingly, c-Jun NH(2)-terminal kinase (JNK) but not XBP-1, both of which are the known downstream targets of IRE1, seemed to participate in autophagy induction by proteasome inhibitors. Finally, proteasome inhibitor-induced autophagy was important for controlling endoplasmic reticulum stress and reducing cell death in cancer cells. Our studies thus provide a mechanistic view and elucidate the functional significance of the link between the two protein degradation systems.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Autophagy / physiology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HCT116 Cells
  • Humans
  • Immunoblotting
  • Leupeptins / pharmacology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Microscopy, Confocal
  • Microscopy, Electron
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Ubiquitin / metabolism*
  • Vacuoles / metabolism
  • Vacuoles / ultrastructure
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • BAX protein, human
  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Proteasome Inhibitors
  • Recombinant Fusion Proteins
  • Ubiquitin
  • bcl-2-Associated X Protein
  • light chain 3, human
  • Green Fluorescent Proteins
  • ERN2 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde