Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 6213K) PDF+supp data (6709K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Clerc, S. Articles by Aebi, M. Search for Related Content PubMed PubMed Citation Articles by Clerc, S. Articles by Aebi, M. Related Collections Related In this Issue article Social Bookmarking                            What's this?

Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum

¹ Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule Zürich, CH-8093 Zürich, Switzerland
² Max Delbrück Center for Molecular Medicine, D-13122 Berlin, Germany

Correspondence to Markus Aebi: aebi{at}micro.biol.ethz.ch

To maintain protein homeostasis in secretory compartments, eukaryotic cells harbor a quality control system that monitors protein folding and protein complex assembly in the endoplasmic reticulum (ER). Proteins that do not fold properly or integrate into cognate complexes are degraded by ER-associated degradation (ERAD) involving retrotranslocation to the cytoplasm and proteasomal peptide hydrolysis. N-linked glycans are essential in glycoprotein ERAD; the covalent oligosaccharide structure is used as a signal to display the folding status of the host protein. In this study, we define the function of the Htm1 protein as an 1,2-specific exomannosidase that generates the Man₇GlcNAc₂ oligosaccharide with a terminal 1,6-linked mannosyl residue on degradation substrates. This oligosaccharide signal is decoded by the ER-localized lectin Yos9p that in conjunction with Hrd3p triggers the ubiquitin-proteasome–dependent hydrolysis of these glycoproteins. The Htm1p exomannosidase activity requires processing of the N-glycan by glucosidase I, glucosidase II, and mannosidase I, resulting in a sequential order of specific N-glycan structures that reflect the folding status of the glycoprotein.

Abbreviations used in this paper: CPY*, carboxypeptidase Y*; EDEM, ER degradation–enhancing -mannosidase–like protein; ERAD, ER-associated degradation; ERAD-L, ERAD–lumen; HXK, hexokinase; LC, liquid chromatography; TAP, tandem affinity purification.

© 2009 Clerc et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

The Rockefeller University Press

CiteULike

Complore

Connotea

Del.icio.us

Digg

Facebook

Reddit

Technorati

Twitter

This article has been cited by other articles:

• Mikami, K., Yamaguchi, D., Tateno, H., Hu, D., Qin, S.-Y., Kawasaki, N., Yamada, M., Matsumoto, N., Hirabayashi, J., Ito, Y., Yamamoto, K. (2010). The sugar-binding ability of human OS-9 and its involvement in ER-associated degradation. Glycobiology 20: 310-321 [Abstract] [Full Text]  
• Yamaguchi, D., Hu, D., Matsumoto, N., Yamamoto, K. (2010). Human XTP3-B binds to {alpha}1-antitrypsin variant nullHong Kong via the C-terminal MRH domain in a glycan-dependent manner. Glycobiology 20: 348-355 [Abstract] [Full Text]  
• Bernasconi, R., Galli, C., Calanca, V., Nakajima, T., Molinari, M. (2010). Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates. JCB 188: 223-235 [Abstract] [Full Text]  
• Hoseki, J., Ushioda, R., Nagata, K. (2010). Mechanism and components of endoplasmic reticulum-associated degradation. J Biochem 147: 19-25 [Abstract] [Full Text]  
• Kosmaoglou, M., Kanuga, N., Aguila, M., Garriga, P., Cheetham, M. E. (2009). A dual role for EDEM1 in the processing of rod opsin. J. Cell Sci. 122: 4465-4472 [Abstract] [Full Text]  
• Cameron, P. H., Chevet, E., Pluquet, O., Thomas, D. Y., Bergeron, J. J. M. (2009). Calnexin Phosphorylation Attenuates the Release of Partially Misfolded {alpha}1-Antitrypsin to the Secretory Pathway. J. Biol. Chem. 284: 34570-34579 [Abstract] [Full Text]  
• Quinn, R. P, Mahoney, S. J, Wilkinson, B. M, Thornton, D. J, Stirling, C. J (2009). A novel role for Gtb1p in glucose trimming of N-linked glycans. Glycobiology 19: 1408-1416 [Abstract] [Full Text]  
• Hong, Z., Jin, H., Fitchette, A.-C., Xia, Y., Monk, A. M., Faye, L., Li, J. (2009). Mutations of an {alpha}1,6 Mannosyltransferase Inhibit Endoplasmic Reticulum-Associated Degradation of Defective Brassinosteroid Receptors in Arabidopsis. Plant Cell 21: 3792-3802 [Abstract] [Full Text]  
• Liebminger, E., Huttner, S., Vavra, U., Fischl, R., Schoberer, J., Grass, J., Blaukopf, C., Seifert, G. J., Altmann, F., Mach, L., Strasser, R. (2009). Class I {alpha}-Mannosidases Are Required for N-Glycan Processing and Root Development in Arabidopsis thaliana. Plant Cell 21: 3850-3867 [Abstract] [Full Text]  
• Kang, M.-J., Ryoo, H. D. (2009). Suppression of retinal degeneration in Drosophila by stimulation of ER-associated degradation. Proc. Natl. Acad. Sci. USA 106: 17043-17048 [Abstract] [Full Text]  
• Vleugels, W., Keldermans, L., Jaeken, J., Butters, T. D, Michalski, J.-C., Matthijs, G., Foulquier, F. (2009). Quality control of glycoproteins bearing truncated glycans in an ALG9-defective (CDG-IL) patient. Glycobiology 19: 910-917 [Abstract] [Full Text]  
• Xie, W., Kanehara, K., Sayeed, A., Ng, D. T.W. (2009). Intrinsic Conformational Determinants Signal Protein Misfolding to the Hrd1/Htm1 Endoplasmic Reticulum-associated Degradation System. Mol. Biol. Cell 20: 3317-3329 [Abstract] [Full Text]  
• Sedwick, C. (2009). Htm1p: getting a "sugar-handle" on misfolded proteins. JCB 184: 2-3 [Full Text]  
• Sakoh-Nakatogawa, M., Nishikawa, S.-i., Endo, T. (2009). Roles of Protein-disulfide Isomerase-mediated Disulfide Bond Formation of Yeast Mnl1p in Endoplasmic Reticulum-associated Degradation. J. Biol. Chem. 284: 11815-11825 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents