Published online before print July 9, 2007

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2007.070188v1 171/2/513    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ding, W.-X. Articles by Yin, X.-M. Search for Related Content PubMed PubMed Citation Articles by Ding, W.-X. Articles by Yin, X.-M.

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.

This article has been cited by other articles:

				D. R. Fels, J. Ye, A. T. Segan, S. J. Kridel, M. Spiotto, M. Olson, A. C. Koong, and C. Koumenis Preferential Cytotoxicity of Bortezomib toward Hypoxic Tumor Cells via Overactivation of Endoplasmic Reticulum Stress Pathways Cancer Res., November 15, 2008; 68(22): 9323 - 9330. [Abstract] [Full Text] [PDF]

				J.-S. Ju, S. E. Miller, P. I. Hanson, and C. C. Weihl Impaired Protein Aggregate Handling and Clearance Underlie the Pathogenesis of p97/VCP-associated Disease J. Biol. Chem., October 31, 2008; 283(44): 30289 - 30299. [Abstract] [Full Text] [PDF]

				R. Khatri and E. Schipani About the importance of being desulfated Genes & Dev., October 15, 2008; 22(20): 2750 - 2754. [Abstract] [Full Text] [PDF]

				A. Melendez and T. P. Neufeld The cell biology of autophagy in metazoans: a developing story Development, July 15, 2008; 135(14): 2347 - 2360. [Abstract] [Full Text] [PDF]