Published online before print July 9, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070188

Accepted for publication May 4, 2007.

Article

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, and Xiao-Ming Yin^*@

From the Departments of Pathology* and Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; the Department of Cell Genetics, National Institute of Genetics, Mishima, Japan; and the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York

^@ To whom correspondence should be addressed. E-mail: xmyin{at}pitt.edu.

	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.

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