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J. Biol. Chem., Vol. 283, Issue 1, 244-254, January 4, 2008

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N-Linked Glycosylation Does Not Impair Proteasomal Degradation but Affects Class I Major Histocompatibility Complex Presentation^*

Edith Kario¹², Boaz Tirosh¹, Hidde L. Ploegh^¶, and Ami Navon, An incumbent of the Recanati career development chair of cancer research³

From the Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel, the Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem 91120, Israel, and the ^¶Whitehead Institute of Biomedical Research, Cambridge, Massachusetts 02142

The addition of N-linked glycans to nascent polypeptides occurs cotranslationally in the endoplasmic reticulum (ER). For many proteins the state of the glycans serves as an indicator, which allows the ER quality control system to monitor the conformation of polypeptides upon folding. Proteins that fail to fold in the ER are often dislocated to the cytoplasm, where they are subjected to proteasomal degradation. Although the addition of N-linked glycans occurs within the ER, non-lysosomal removal of the glycans occurs in the cytosol by the action of peptide N-glycanase (PNGase). In this study, we investigated the interplay between PNGase action and proteasomal degradation of ER misfolded proteins (i.e. whether PNGase acts prior to or following proteasomal degradation). Interestingly, we found that glycan removal from N-terminally extended peptides modulates the presentation of class I major histocompatibility complex-restricted epitopes. Our findings provide direct evidence that the proteasome is capable of degrading glycoproteins without prior removal of their glycans. This degradation is independent of either the identity of the glycosylated protein or the type and number of N-linked glycans it harbors. We also captured and characterized glycopeptides generated following proteasomal degradation of RNaseB. Although the carbohydrate moiety reduced the variability of the degradation products that include the glycosylated residue (local effect), the overall global digestion pattern of RNaseB was unaffected. Together with earlier findings by others, our data support a model in which PNGase may act both upstream and downstream to proteasomal degradation and demonstrates its important role in class I major histocompatibility complex antigen presentation.

Received for publication, July 30, 2007 , and in revised form, October 10, 2007.

^* This work was supported in part by the Israeli Foundation of Science (Grant ISF 802/04), The German Minerva foundation (Grant 8527), the German Israeli Foundation for scientific research and development (Grant GIF I-845-210.9/2004), and a special donation from Rolando Uziel. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S7.

¹ Both authors contributed equally to this work.

² A recipient of an Eshkol PhD fellowship (3-3407).

³ To whom correspondence should be addressed: Tel.: 972-8-934-3719; Fax: 972-8-934-4116; E-mail: ami.navon{at}weizmann.ac.il.

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