Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability.
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.
Ding
Wen-Xing
WX
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231, USA.
Ni
Hong-Min
HM
Gao
Wentao
W
Yoshimori
Tamotsu
T
Stolz
Donna B
DB
Ron
David
D
Yin
Xiao-Ming
XM
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D007976:Leupeptins / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
C494826:BAX protein, human; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D061988:Proteasome Inhibitors; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde