Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 171, Issue 2, Pages 513-524Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2007.070188
Keywords
-
Categories
Funding
- NCI NIH HHS [R01 CA083817, R01 CA111456, CA83817, CA111456] Funding Source: Medline
- NIDDK NIH HHS [R37 DK047119, R01 DK047119, DK47119] Funding Source: Medline
- NIEHS NIH HHS [ES0861] Funding Source: Medline
- NINDS NIH HHS [R01 NS045252, NS45252] Funding Source: Medline
Ask authors/readers for more resources
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 NH2-terminal kinase (INK) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available