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

Wen Xing Ding, Hong Min Ni, Wentao Gao, Tamotsu Yoshimori, Donna B. Stolz, David Ron, Xiao Ming Yin

Research output: Contribution to journalArticle

488 Citations (Scopus)

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 NH2-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.

Original languageEnglish (US)
Pages (from-to)513-524
Number of pages12
JournalAmerican Journal of Pathology
Volume171
Issue number2
DOIs
StatePublished - Aug 2007

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Endoplasmic Reticulum Stress
Autophagy
Proteasome Endopeptidase Complex
Ubiquitin
Cell Survival
Proteasome Inhibitors
Proteolysis
Unfolded Protein Response
JNK Mitogen-Activated Protein Kinases
Gene Deletion
RNA Interference
Cell Death

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. / Ding, Wen Xing; Ni, Hong Min; Gao, Wentao; Yoshimori, Tamotsu; Stolz, Donna B.; Ron, David; Yin, Xiao Ming.

In: American Journal of Pathology, Vol. 171, No. 2, 08.2007, p. 513-524.

Research output: Contribution to journalArticle

Ding, Wen Xing ; Ni, Hong Min ; Gao, Wentao ; Yoshimori, Tamotsu ; Stolz, Donna B. ; Ron, David ; Yin, Xiao Ming. / Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. In: American Journal of Pathology. 2007 ; Vol. 171, No. 2. pp. 513-524.
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