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Glycoprotein misfolding in the endoplasmic reticulum: identification of released oligosaccharides reveals a second ER-associated degradation pathway for Golgi-retrieved proteins

Alonzi, Dominic S.; Kukushkin, Nikolay V.; Allman, Sarah A.; Hakki, Zalihe; Williams, Spencer J.; Pierce, Lorna; Dwek, Raymond A. and Butters, Terry D. (2013). Glycoprotein misfolding in the endoplasmic reticulum: identification of released oligosaccharides reveals a second ER-associated degradation pathway for Golgi-retrieved proteins. Cellular and Molecular Life Sciences, 70(15) pp. 2799–2814.

DOI (Digital Object Identifier) Link: https://doi.org/10.1007/s00018-013-1304-6
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Abstract

Endoplasmic reticulum-associated degradation (ERAD) is a key cellular process whereby misfolded proteins are removed from the endoplasmic reticulum (ER) for subsequent degradation by the ubiquitin/proteasome system. In the present work, analysis of the released, free oligosaccharides (FOS) derived from all glycoproteins undergoing ERAD, has allowed a global estimation of the mechanisms of this pathway rather than following model proteins through degradative routes. Examining the FOS produced in endomannosidase-compromised cells following α-glucosidase inhibition has revealed a mechanism for clearing Golgi-retrieved glycoproteins that have failed to enter the ER quality control cycle. The Glc3Man7GlcNAc2 FOS species has been shown to be produced in the ER lumen by a mechanism involving a peptide: N-glycanase-like activity, and its production was sensitive to disruption of Golgi-ER trafficking. The detection of this oligosaccharide was unaffected by the overexpression of EDEM1 or cytosolic mannosidase, both of which increased the production of previously characterised cytosolically localised FOS. The lumenal FOS identified are therefore distinct in their production and regulation compared to FOS produced by the conventional route of misfolded glycoproteins directly removed from the ER. The production of such lumenal FOS is indicative of a novel degradative route for cellular glycoproteins that may exist under certain conditions.

Item Type: Journal Item
Copyright Holders: 2013 Springer Basel
ISSN: 1420-682X
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetNot SetOxford Glycobiology Institute
Not SetNot SetAustralian Research Council
Not SetNot SetClarendon Fund/New College (Robert Lyns)
Keywords: ER-associated degradation; free oligosaccharides; N-glycosylation; quality control; MAN2C1; EDEM
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 38114
Depositing User: Sarah Allman
Date Deposited: 07 Aug 2013 11:28
Last Modified: 07 Dec 2018 10:17
URI: http://oro.open.ac.uk/id/eprint/38114
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