Home LiteratureArticle Details
PMID: 19398763 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

K63-linked ubiquitin chains as a specific signal for protein sorting into the multivesicular body pathway.

The Journal of cell biology ·Vol. 185 ·No. 3 ·2009-05-04 ·Pages 493-502

Lauwers E, Jacob C, André B

Abstract

A growing number of yeast and mammalian plasma membrane proteins are reported to be modified with K63-linked ubiquitin (Ub) chains. However, the relative importance of this modification versus monoubiquitylation in endocytosis, Golgi to endosome traffic, and sorting into the multivesicular body (MVB) pathway remains unclear. In this study, we show that K63-linked ubiquitylation of the Gap1 permease is essential for its entry into the MVB pathway. Carboxypeptidase S also requires modification with a K63-Ub chain for correct MVB sorting. In contrast, monoubiquitylation of a single target lysine of Gap1 is a sufficient signal for its internalization from the cell surface, and Golgi to endosome transport of the permease requires neither its ubiquitylation nor the Ub-binding GAT (Gga and Tom1) domain of Gga (Golgi localizing, gamma-ear containing, ARF binding) adapter proteins, the latter being crucial for subsequent MVB sorting of the permease. Our data reveal that K63-linked Ub chains act as a specific signal for MVB sorting, providing further insight into the Ub code of membrane protein trafficking.

MeSH Terms
Amino Acid Transport Systems/metabolism Animals Cell Membrane/physiology Endocytosis/physiology Endosomes/physiology Golgi Apparatus/physiology Mammals Membrane Proteins/physiology Protein Sorting Signals/physiology Saccharomyces cerevisiae/physiology Saccharomyces cerevisiae Proteins/metabolism Ubiquitin/physiology
Chemicals
Amino Acid Transport Systems GAP1 protein, S cerevisiae Membrane Proteins Protein Sorting Signals Saccharomyces cerevisiae Proteins Ubiquitin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Lauwers Elsa
Laboratoire de Physiologie Moléculaire de la Cellule, Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium.
Jacob Christophe
André Bruno
References (62)
62 references, click to expand
  1. Transferrin receptor-like proteins control the degradation of a yeast metal transporter.
    EMBO J. 2006 Feb 22;25(4):662-72 PMID: 16456538
  2. Ubiquitin is required for sorting to the vacuole of the yeast general amino acid permease, Gap1.
    J Biol Chem. 2001 Nov 23;276(47):43949-57 PMID: 11500494
  3. Multiplicity of the amino acid permeases in Saccharomyces cerevisiae. I. Evidence for a specific arginine-transporting system.
    Biochim Biophys Acta. 1966 Oct 31;127(2):325-38 PMID: 5964977
  4. The novel functions of ubiquitination in signaling.
    Curr Opin Cell Biol. 2004 Apr;16(2):119-26 PMID: 15196553
  5. Yeast Gga coat proteins function with clathrin in Golgi to endosome transport.
    Mol Biol Cell. 2001 Jun;12(6):1885-96 PMID: 11408593
  6. Endocytosis: the DUB version.
    Trends Cell Biol. 2006 Nov;16(11):551-9 PMID: 16996268
  7. Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules.
    EMBO J. 2006 Apr 19;25(8):1635-45 PMID: 16601694
  8. Protein regulation by monoubiquitin.
    Nat Rev Mol Cell Biol. 2001 Mar;2(3):195-201 PMID: 11265249
  9. Ubiquitin sorts proteins into the intralumenal degradative compartment of the late-endosome/vacuole.
    Traffic. 2001 Sep;2(9):622-30 PMID: 11555416
  10. Stress resistance in Saccharomyces cerevisiae is strongly correlated with assembly of a novel type of multiubiquitin chain.
    Mol Cell Biol. 1994 Dec;14(12):7876-83 PMID: 7969127
  11. The GGA proteins: adaptors on the move.
    Nat Rev Mol Cell Biol. 2004 Jan;5(1):23-32 PMID: 14708007
  12. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I.
    Cell. 2001 Jul 27;106(2):145-55 PMID: 11511343
  13. The Vps27p Hse1p complex binds ubiquitin and mediates endosomal protein sorting.
    Nat Cell Biol. 2002 Jul;4(7):534-9 PMID: 12055639
  14. The GAT domains of clathrin-associated GGA proteins have two ubiquitin binding motifs.
    J Biol Chem. 2004 Dec 24;279(52):54808-16 PMID: 15494413
  15. Polyubiquitin chains: polymeric protein signals.
    Curr Opin Chem Biol. 2004 Dec;8(6):610-6 PMID: 15556404
  16. The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme.
    EMBO J. 2005 Jul 6;24(13):2414-24 PMID: 15933713
  17. A subset of yeast vacuolar protein sorting mutants is blocked in one branch of the exocytic pathway.
    J Cell Biol. 2002 Jan 21;156(2):271-85 PMID: 11807092
  18. NH4+-induced down-regulation of the Saccharomyces cerevisiae Gap1p permease involves its ubiquitination with lysine-63-linked chains.
    J Cell Sci. 1999 May;112 ( Pt 9):1375-83 PMID: 10194416
  19. Decoding ubiquitin sorting signals for clathrin-dependent endocytosis by CLASPs.
    J Cell Sci. 2007 Feb 15;120(Pt 4):543-53 PMID: 17287393
  20. GGA2- and ubiquitin-dependent trafficking of Arn1, the ferrichrome transporter of Saccharomyces cerevisiae.
    Mol Biol Cell. 2007 May;18(5):1790-802 PMID: 17344478
  21. Substrate- and ubiquitin-dependent trafficking of the yeast siderophore transporter Sit1.
    Traffic. 2008 Aug;9(8):1372-91 PMID: 18489705
  22. Characterization of multiple multivesicular body sorting determinants within Sna3: a role for the ubiquitin ligase Rsp5.
    Mol Biol Cell. 2007 Feb;18(2):707-20 PMID: 17182849
  23. Yeast and human Ysl2p/hMon2 interact with Gga adaptors and mediate their subcellular distribution.
    EMBO J. 2008 May 21;27(10):1423-35 PMID: 18418388
  24. Multivesicular body sorting: ubiquitin ligase Rsp5 is required for the modification and sorting of carboxypeptidase S.
    Mol Biol Cell. 2004 Feb;15(2):468-80 PMID: 14657247
  25. Evidence for a direct role of the Doa4 deubiquitinating enzyme in protein sorting into the MVB pathway.
    Traffic. 2007 May;8(5):566-81 PMID: 17376168
  26. Plasticity of polyubiquitin recognition as lysosomal targeting signals by the endosomal sorting machinery.
    Mol Biol Cell. 2007 Oct;18(10):3952-65 PMID: 17686993
  27. Direct binding to Rsp5p regulates ubiquitination-independent vacuolar transport of Sna3p.
    Mol Biol Cell. 2007 May;18(5):1781-9 PMID: 17332499
  28. A cis-dominant regulatory mutation linked to the argB-argC gene cluster in Saccharomyces cerevisiae.
    J Mol Biol. 1980 Jun 5;139(4):691-704 PMID: 6251229
  29. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain.
    Mol Cell. 2006 Mar 17;21(6):737-48 PMID: 16543144
  30. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination.
    Mol Cell Biol. 1995 Mar;15(3):1265-73 PMID: 7862120
  31. Different ubiquitin signals act at the Golgi and plasma membrane to direct GAP1 trafficking.
    Mol Biol Cell. 2008 Jul;19(7):2962-72 PMID: 18434603
  32. SEC7 encodes an unusual, high molecular weight protein required for membrane traffic from the yeast Golgi apparatus.
    J Biol Chem. 1988 Aug 25;263(24):11711-7 PMID: 3042778
  33. Direct binding to Rsp5 mediates ubiquitin-independent sorting of Sna3 via the multivesicular body pathway.
    Mol Biol Cell. 2007 Feb;18(2):697-706 PMID: 17182850
  34. Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling.
    Mol Cell. 2005 Oct 28;20(2):301-12 PMID: 16246731
  35. Ubiquitin-mediated targeting of a mutant plasma membrane ATPase, Pma1-7, to the endosomal/vacuolar system in yeast.
    Mol Biol Cell. 2004 May;15(5):2401-9 PMID: 15020711
  36. Starvation induces vacuolar targeting and degradation of the tryptophan permease in yeast.
    J Cell Biol. 1999 Sep 20;146(6):1227-38 PMID: 10491387
  37. Evidence for coupled biogenesis of yeast Gap1 permease and sphingolipids: essential role in transport activity and normal control by ubiquitination.
    Mol Biol Cell. 2007 Aug;18(8):3068-80 PMID: 17553927
  38. Polyubiquitination of prolactin receptor stimulates its internalization, postinternalization sorting, and degradation via the lysosomal pathway.
    Mol Cell Biol. 2008 Sep;28(17):5275-87 PMID: 18573876
  39. A proteomics approach to understanding protein ubiquitination.
    Nat Biotechnol. 2003 Aug;21(8):921-6 PMID: 12872131
  40. Short-chain ubiquitination mediates the regulated endocytosis of the aquaporin-2 water channel.
    Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18344-9 PMID: 17101973
  41. Permease recycling and ubiquitination status reveal a particular role for Bro1 in the multivesicular body pathway.
    J Biol Chem. 2003 Dec 12;278(50):50732-43 PMID: 14523026
  42. Sorting of proteins into multivesicular bodies: ubiquitin-dependent and -independent targeting.
    EMBO J. 2001 Sep 17;20(18):5176-86 PMID: 11566881
  43. Targeting of Sna3p to the endosomal pathway depends on its interaction with Rsp5p and multivesicular body sorting on its ubiquitylation.
    Traffic. 2007 Sep;8(9):1280-96 PMID: 17645729
  44. Dual mechanisms specify Doa4-mediated deubiquitination at multivesicular bodies.
    EMBO J. 2007 May 16;26(10):2454-64 PMID: 17446860
  45. Ergosterol is required for targeting of tryptophan permease to the yeast plasma membrane.
    J Cell Biol. 2003 Jun 23;161(6):1117-31 PMID: 12810702
  46. Direct sorting of the yeast uracil permease to the endosomal system is controlled by uracil binding and Rsp5p-dependent ubiquitylation.
    Mol Biol Cell. 2004 Feb;15(2):883-95 PMID: 14657252
  47. NPl1, an essential yeast gene involved in induced degradation of Gap1 and Fur4 permeases, encodes the Rsp5 ubiquitin-protein ligase.
    Mol Microbiol. 1995 Oct;18(1):77-87 PMID: 8596462
  48. Ubiquitin lys63 is involved in ubiquitination of a yeast plasma membrane protein.
    EMBO J. 1997 Oct 1;16(19):5847-54 PMID: 9312043
  49. A protein's final ESCRT.
    Traffic. 2005 Jan;6(1):2-9 PMID: 15569240
  50. Nitrogen-regulated ubiquitination of the Gap1 permease of Saccharomyces cerevisiae.
    Mol Biol Cell. 1998 Jun;9(6):1253-63 PMID: 9614172
  51. Physiological regulation of membrane protein sorting late in the secretory pathway of Saccharomyces cerevisiae.
    J Cell Biol. 1997 Jun 30;137(7):1469-82 PMID: 9199164
  52. The Saccharomyces cerevisiae SEC14 gene encodes a cytosolic factor that is required for transport of secretory proteins from the yeast Golgi complex.
    J Cell Biol. 1989 Apr;108(4):1271-81 PMID: 2466847
  53. Recognition of the polyubiquitin proteolytic signal.
    EMBO J. 2000 Jan 4;19(1):94-102 PMID: 10619848
  54. Interactions of GGA3 with the ubiquitin sorting machinery.
    Nat Cell Biol. 2004 Mar;6(3):244-51 PMID: 15039775
  55. Dynamin and clathrin are required for the biogenesis of a distinct class of secretory vesicles in yeast.
    EMBO J. 2002 Feb 15;21(4):602-14 PMID: 11847108
  56. Epsin 1 is a polyubiquitin-selective clathrin-associated sorting protein.
    Traffic. 2006 Mar;7(3):262-81 PMID: 16497222
  57. Proteasome-independent functions of ubiquitin in endocytosis and signaling.
    Science. 2007 Jan 12;315(5809):201-5 PMID: 17218518
  58. Components of a ubiquitin ligase complex specify polyubiquitination and intracellular trafficking of the general amino acid permease.
    J Cell Biol. 2001 May 14;153(4):649-62 PMID: 11352928
  59. The deubiquitinating enzyme Ubp2 modulates Rsp5-dependent Lys63-linked polyubiquitin conjugates in Saccharomyces cerevisiae.
    J Biol Chem. 2006 Dec 1;281(48):36724-31 PMID: 17028178
  60. GGA proteins bind ubiquitin to facilitate sorting at the trans-Golgi network.
    Nat Cell Biol. 2004 Mar;6(3):252-9 PMID: 15039776
  61. The Npr1 kinase controls biosynthetic and endocytic sorting of the yeast Gap1 permease.
    J Biol Chem. 2001 Nov 23;276(47):43939-48 PMID: 11500493
  62. Gettin' down with ubiquitin: turning off cell-surface receptors, transporters and channels.
    Trends Cell Biol. 1999 Mar;9(3):107-12 PMID: 10201076
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200810114
Published
2009-05-04
Epub
2009-00-27
Pages
493-502
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2700384
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200810114 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: product@genelibs.com

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