Home LiteratureArticle Details
PMID: 15809311 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation.

The Journal of cell biology ·Vol. 169 ·No. 1 ·2005-04-11 ·Pages 73-82

Spear ED, Ng DT

Abstract

The endoplasmic reticulum (ER) maintains an environment essential for secretory protein folding. Consequently, the premature transport of polypeptides would be harmful to the cell. To avert this scenario, mechanisms collectively termed "ER quality control" prevent the transport of nascent polypeptides until they properly fold. Irreversibly misfolded molecules are sorted for disposal by the ER-associated degradation (ERAD) pathway. To better understand the relationship between quality control and ERAD, we studied a new misfolded variant of carboxypeptidase Y (CPY). The molecule was recognized and retained by ER quality control but failed to enter the ERAD pathway. Systematic analysis revealed that a single, specific N-linked glycan of CPY was required for sorting into the pathway. The determinant is dependent on the putative lectin-like receptor Htm1/Mnl1p. The discovery of a similar signal in misfolded proteinase A supported the generality of the mechanism. These studies show that specific signals embedded in glycoproteins can direct their degradation if they fail to fold.

MeSH Terms
Aspartic Acid Endopeptidases/genetics,metabolism Cathepsin A/genetics,metabolism Endoplasmic Reticulum/genetics,physiology Glycoproteins/genetics,metabolism Glycosylation Mannosidases/genetics,metabolism Polysaccharides Protein Folding Protein Sorting Signals/genetics,physiology Protein Transport Saccharomyces cerevisiae/genetics,physiology Saccharomyces cerevisiae Proteins/genetics,metabolism
Chemicals
Glycoproteins Polysaccharides Protein Sorting Signals Saccharomyces cerevisiae Proteins MNL1 protein, S cerevisiae Mannosidases Cathepsin A Aspartic Acid Endopeptidases aspergillopepsin II
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Spear Eric D
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Ng Davis T W
References (45)
45 references, click to expand
  1. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48.
    Nat Cell Biol. 2002 Feb;4(2):134-9 PMID: 11813000
  2. Stress tolerance of misfolded carboxypeptidase Y requires maintenance of protein trafficking and degradative pathways.
    Mol Biol Cell. 2003 Jul;14(7):2756-67 PMID: 12857862
  3. S. cerevisiae encodes an essential protein homologous in sequence and function to mammalian BiP.
    Cell. 1989 Jun 30;57(7):1223-36 PMID: 2661019
  4. A membrane protein required for dislocation of misfolded proteins from the ER.
    Nature. 2004 Jun 24;429(6994):834-40 PMID: 15215855
  5. A role for N-glycanase in the cytosolic turnover of glycoproteins.
    EMBO J. 2003 Mar 3;22(5):1036-46 PMID: 12606569
  6. Overview of N- and O-linked oligosaccharide structures found in various yeast species.
    Biochim Biophys Acta. 1999 Jan 6;1426(2):227-37 PMID: 9878752
  7. Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals.
    Curr Opin Cell Biol. 2001 Jun;13(3):349-55 PMID: 11343907
  8. Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure.
    J Cell Biol. 1998 Sep 7;142(5):1223-33 PMID: 9732283
  9. Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast.
    EMBO Rep. 2001 May;2(5):423-30 PMID: 11375935
  10. Analysis of two mutated vacuolar proteins reveals a degradation pathway in the endoplasmic reticulum or a related compartment of yeast.
    Eur J Biochem. 1993 Dec 1;218(2):565-74 PMID: 8269947
  11. Different roles of individual N-linked oligosaccharide chains in folding, assembly, and transport of the simian virus 5 hemagglutinin-neuraminidase.
    Mol Cell Biol. 1990 May;10(5):1989-2001 PMID: 2183015
  12. Generation of a lysosomal enzyme targeting signal in the secretory protein pepsinogen.
    Cell. 1990 Oct 19;63(2):281-91 PMID: 2170024
  13. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol.
    Nature. 2001 Dec 6;414(6864):652-6 PMID: 11740563
  14. Distinct retrieval and retention mechanisms are required for the quality control of endoplasmic reticulum protein folding.
    J Cell Biol. 2001 Oct 29;155(3):355-68 PMID: 11673477
  15. KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP/GRP78 gene.
    Cell. 1989 Jun 30;57(7):1211-21 PMID: 2661018
  16. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase.
    Cell. 1993 Jun 18;73(6):1197-206 PMID: 8513503
  17. N-Glycosylation affects endoplasmic reticulum degradation of a mutated derivative of carboxypeptidase yscY in yeast.
    Yeast. 1996 Sep 30;12(12):1229-38 PMID: 8905927
  18. PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase.
    J Cell Biol. 2000 May 29;149(5):1039-52 PMID: 10831608
  19. The PEP4 gene encodes an aspartyl protease implicated in the posttranslational regulation of Saccharomyces cerevisiae vacuolar hydrolases.
    Mol Cell Biol. 1986 Jul;6(7):2500-10 PMID: 3537721
  20. Endoplasmic reticulum (ER)-associated degradation of misfolded N-linked glycoproteins is suppressed upon inhibition of ER mannosidase I.
    J Biol Chem. 2000 Dec 29;275(52):40757-64 PMID: 10984471
  21. A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion.
    Cell. 1998 Jun 26;93(7):1241-52 PMID: 9657156
  22. Evolving questions and paradigm shifts in endoplasmic-reticulum-associated degradation (ERAD).
    Bioessays. 2003 Sep;25(9):868-77 PMID: 12938176
  23. A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation.
    EMBO Rep. 2001 May;2(5):415-22 PMID: 11375934
  24. Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation.
    J Cell Sci. 1999 Nov;112 ( Pt 22):4123-34 PMID: 10547371
  25. Quality control in the endoplasmic reticulum protein factory.
    Nature. 2003 Dec 18;426(6968):891-4 PMID: 14685249
  26. 2.8-A structure of yeast serine carboxypeptidase.
    Biochemistry. 1994 Sep 20;33(37):11106-20 PMID: 7727362
  27. The unfolded protein response regulates multiple aspects of secretory and membrane protein biogenesis and endoplasmic reticulum quality control.
    J Cell Biol. 2000 Jul 10;150(1):77-88 PMID: 10893258
  28. Quality control and protein folding in the secretory pathway.
    Annu Rev Cell Dev Biol. 2003;19:649-76 PMID: 14570585
  29. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol.
    Nature. 2004 Jun 24;429(6994):841-7 PMID: 15215856
  30. The unfolded protein response: no longer just a special teams player.
    Traffic. 2001 Aug;2(8):515-23 PMID: 11489209
  31. Secretory pathway quality control operating in Golgi, plasmalemmal, and endosomal systems.
    Traffic. 2002 Nov;3(11):771-80 PMID: 12383343
  32. Role of Cue1p in ubiquitination and degradation at the ER surface.
    Science. 1997 Dec 5;278(5344):1806-9 PMID: 9388185
  33. Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle.
    Science. 2003 Feb 28;299(5611):1397-400 PMID: 12610306
  34. EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin.
    Science. 2003 Feb 28;299(5611):1394-7 PMID: 12610305
  35. Mnl1p, an alpha -mannosidase-like protein in yeast Saccharomyces cerevisiae, is required for endoplasmic reticulum-associated degradation of glycoproteins.
    J Biol Chem. 2001 Mar 23;276(12):8635-8 PMID: 11254655
  36. A trip to the ER: coping with stress.
    Trends Cell Biol. 2004 Jan;14(1):20-8 PMID: 14729177
  37. A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae.
    Genetics. 1989 May;122(1):19-27 PMID: 2659436
  38. Polyubiquitination is required for US11-dependent movement of MHC class I heavy chain from endoplasmic reticulum into cytosol.
    Mol Biol Cell. 2001 Aug;12(8):2546-55 PMID: 11514634
  39. Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation.
    J Cell Biol. 2001 May 28;153(5):1061-70 PMID: 11381090
  40. Signal sequences specify the targeting route to the endoplasmic reticulum membrane.
    J Cell Biol. 1996 Jul;134(2):269-78 PMID: 8707814
  41. An HRD/DER-independent ER quality control mechanism involves Rsp5p-dependent ubiquitination and ER-Golgi transport.
    J Cell Biol. 2002 Jul 8;158(1):91-101 PMID: 12105183
  42. Sec61p mediates export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation.
    EMBO J. 1997 Aug 1;16(15):4540-8 PMID: 9303298
  43. Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control.
    J Cell Biol. 2004 Apr;165(1):41-52 PMID: 15078901
  44. Ste6p mutants defective in exit from the endoplasmic reticulum (ER) reveal aspects of an ER quality control pathway in Saccharomyces cerevisiae.
    Mol Biol Cell. 1998 Oct;9(10):2767-84 PMID: 9763443
  45. Quality control in the endoplasmic reticulum.
    Nat Rev Mol Cell Biol. 2003 Mar;4(3):181-91 PMID: 12612637
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200411136
Published
2005-04-11
Epub
2005-00-04
Pages
73-82
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2171888
Subset
IM
Grants
NIGMS NIH HHS · R01 GM059171 · United States
NIGMS NIH HHS · GM059171 · United States
External Links
PubMed source DOI: 10.1083/jcb.200411136 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2