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First published online 3 March 2009
doi: 10.1242/jcs.037291

Journal of Cell Science 122, 976-984 (2009)
Published by The Company of Biologists 2009
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Research Article

The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I

Daniel J. Termine1, Kelley W. Moremen2,3 and Richard N. Sifers1,4,5,*

1 Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
5 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
2 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
3 Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA

* Author for correspondence (e-mail: rsifers{at}bcm.edu)

Accepted 1 December 2008

The secretory pathway provides a physical route through which only correctly folded gene products are delivered to the eukaryotic cell surface. The efficiency of endoplasmic reticulum (ER)-associated degradation (ERAD), which orchestrates the clearance of structurally aberrant proteins under basal conditions, is boosted by the unfolded protein response (UPR) as one of several means to relieve ER stress. However, the underlying mechanism that links the two systems in higher eukaryotes has remained elusive. Herein, the results of transient expression, RNAi-mediated knockdown and functional studies demonstrate that the transcriptional elevation of EDEM1 boosts the efficiency of glycoprotein ERAD through the formation of a complex that suppresses the proteolytic downregulation of ER mannosidase I (ERManI). The results of site-directed mutagenesis indicate that this capacity does not require that EDEM1 possess inherent mannosidase activity. A model is proposed in which ERManI, by functioning as a downstream effector target of EDEM1, represents a checkpoint activation paradigm by which the mammalian UPR coordinates the boosting of ERAD.

Key words: Checkpoint activation, Endoplasmic reticulum-associated degradation, Unfolded protein response


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