Skip to main content
SpringerLink
Log in

Regulation of Endocytic Sorting by ESCRT–DUB-Mediated Deubiquitination

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Endocytosis of cell surface receptors mediates cellular homeostasis by coordinating receptor distribution with downstream signal transduction and attenuation. Post-translational modification with ubiquitin of these receptors, as well as the proteins that comprise the endocytic machinery, modulates cargo progression along the endocytic pathway. The interplay between ubiquitination states of cargo and sorting proteins drives trafficking outcomes by directing endocytosed material toward either lysosomal degradation or recycling. Deubiquitination by specific proteinases creates a reversible system that promotes spatial and temporal organization of endosomal sorting complexes required for transport (ESCRTs) and supports regulated cargo trafficking. Two dubiquitinating enzymes—ubiquitin-specific protease 8 (USP8/Ubpy) and associated molecule with the SH3 domain of STAM (AMSH)—interact with ESCRT components to modulate the ubiquitination status of receptors and relevant sorting proteins. In doing so, these ESCRT–DUBs control receptor fate and sorting complex function through a variety of mechanisms described herein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Jovic, M., Sharma, M., Rahajeng, J., & Caplan, S. (2010). The early endosome: A busy sorting station for proteins at the crossroads. Histology and Histopathology, 25, 99–112.

    PubMed  CAS  Google Scholar 

  2. Waterman, H., & Yarden, Y. (2001). Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases. FEBS Letters, 490, 142–152.

    Article  PubMed  CAS  Google Scholar 

  3. Duncan, L. M., Piper, S., Dodd, R. B., Saville, M. K., Sanderson, C. M., Luzio, J. P., et al. (2006). Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules. EMBO Journal, 25, 1635–1645.

    Article  PubMed  CAS  Google Scholar 

  4. Galan, J. M., & Haguenauer-Tsapis, R. (1997). Ubiquitin lys63 is involved in ubiquitination of a yeast plasma membrane protein. EMBO Journal, 16, 5847–5854.

    Article  PubMed  CAS  Google Scholar 

  5. Geetha, T., Jiang, J., & Wooten, M. W. (2005). Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Molecular Cell, 20, 301–312.

    Article  PubMed  CAS  Google Scholar 

  6. Hicke, L., & Dunn, R. (2003). Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annual Review of Cell and Developmental Biology, 19, 141–172.

    Article  PubMed  CAS  Google Scholar 

  7. Pickart, C. M., & Fushman, D. (2004). Polyubiquitin chains: Polymeric protein signals. Current Opinion Chemical Biology, 8, 610–616.

    Article  CAS  Google Scholar 

  8. Kirisako, T., Ichimura, Y., Okada, H., Kabeya, Y., Mizushima, N., Yoshimori, T., et al. (2000). The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. Journal of Cell Biology, 151, 263–276.

    Article  PubMed  CAS  Google Scholar 

  9. Urbe, S., McCullough, J., Row, P., Prior, I. A., Welchman, R., & Clague, M. J. (2006). Control of growth factor receptor dynamics by reversible ubiquitination. Biochemical Society Transactions, 34, 754–756.

    Article  PubMed  CAS  Google Scholar 

  10. Dikic, I., Wakatsuki, S., & Walters, K. J. (2009). Ubiquitin-binding domains—from structures to functions. Nature Reviews Molecular Cell Biology, 10, 659–671.

    Article  PubMed  CAS  Google Scholar 

  11. Ardley, H. C., & Robinson, P. A. (2005). E3 ubiquitin ligases. Essays in Biochemistry, 41, 15–30.

    Article  PubMed  CAS  Google Scholar 

  12. Deshaies, R. J., & Joazeiro, C. A. (2009). RING domain E3 ubiquitin ligases. Annual Review of Biochemistry, 78, 399–434.

    Article  PubMed  CAS  Google Scholar 

  13. Magnifico, A., Ettenberg, S., Yang, C., Mariano, J., Tiwari, S., Fang, S., et al. (2003). WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation. Journal of Biological Chemistry, 278, 43169–43177.

    Article  PubMed  CAS  Google Scholar 

  14. Wang, J., & Pantopoulos, K. (2005). The pathway for IRP2 degradation involving 2-oxoglutarate-dependent oxygenase(s) does not require the E3 ubiquitin ligase activity of pVHL. Biochimica et Biophysica Acta, 1743, 79–85.

    Article  PubMed  CAS  Google Scholar 

  15. Amerik, A. Y., & Hochstrasser, M. (2004). Mechanism and function of deubiquitinating enzymes. Biochimica et Biophysica Acta, 1695, 189–207.

    Article  PubMed  CAS  Google Scholar 

  16. Nijman, S. M., Huang, T. T., Dirac, A. M., Brummelkamp, T. R., Kerkhoven, R. M., D’Andrea, A. D., et al. (2005). The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Molecular Cell, 17, 331–339.

    Article  PubMed  CAS  Google Scholar 

  17. Nijman, S. M., Luna-Vargas, M. P., Velds, A., Brummelkamp, T. R., Dirac, A. M., Sixma, T. K., et al. (2005). A genomic and functional inventory of deubiquitinating enzymes. Cell, 123, 773–786.

    Article  PubMed  CAS  Google Scholar 

  18. Komander, D., Clague, M. J., & Urbe, S. (2009). Breaking the chains: Structure and function of the deubiquitinases. Nature Reviews Molecular Cell Biology, 10, 550–563.

    Article  PubMed  CAS  Google Scholar 

  19. Wilkinson, K. D., Tashayev, V. L., O’Connor, L. B., Larsen, C. N., Kasperek, E., & Pickart, C. M. (1995). Metabolism of the polyubiquitin degradation signal: Structure, mechanism, and role of isopeptidase T. Biochemistry, 34, 14535–14546.

    Article  PubMed  CAS  Google Scholar 

  20. Reyes-Turcu, F. E., Ventii, K. H., & Wilkinson, K. D. (2009). Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annual Review of Biochemistry, 78, 363–397.

    Article  PubMed  CAS  Google Scholar 

  21. Ren, J., Kee, Y., Huibregtse, J. M., & Piper, R. C. (2007). Hse1, a component of the yeast Hrs-STAM ubiquitin-sorting complex, associates with ubiquitin peptidases and a ligase to control sorting efficiency into multivesicular bodies. Molecular Biology of the Cell, 18, 324–335.

    Article  PubMed  CAS  Google Scholar 

  22. Ren, X., Kloer, D. P., Kim, Y. C., Ghirlando, R., Saidi, L. F., Hummer, G., et al. (2009). Hybrid structural model of the complete human ESCRT-0 complex. Structure, 17, 406–416.

    Article  PubMed  CAS  Google Scholar 

  23. Pawson, T., & Nash, P. (2003). Assembly of cell regulatory systems through protein interaction domains. Science, 300, 445–452.

    Article  PubMed  CAS  Google Scholar 

  24. Katz, E. J., Isasa, M., & Crosas, B. (2010). A new map to understand deubiquitination. Biochemical Society Transactions, 38, 21–28.

    Article  PubMed  CAS  Google Scholar 

  25. Coornaert, B., Baens, M., Heyninck, K., Bekaert, T., Haegman, M., Staal, J., et al. (2008). T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nature Immunology, 9, 263–271.

    Article  PubMed  CAS  Google Scholar 

  26. Wertz, I. E., O’Rourke, K. M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., et al. (2004). De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature, 430, 694–699.

    Article  PubMed  CAS  Google Scholar 

  27. Boone, D. L., Turer, E. E., Lee, E. G., Ahmad, R. C., Wheeler, M. T., Tsui, C., et al. (2004). The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nature Immunology, 5, 1052–1060.

    Article  PubMed  CAS  Google Scholar 

  28. Lee, E. G., Boone, D. L., Chai, S., Libby, S. L., Chien, M., Lodolce, J. P., et al. (2000). Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science, 289, 2350–2354.

    Article  PubMed  CAS  Google Scholar 

  29. Kato, M., Sanada, M., Kato, I., Sato, Y., Takita, J., Takeuchi, K., et al. (2009). Frequent inactivation of A20 in B-cell lymphomas. Nature, 459, 712–716.

    Article  PubMed  CAS  Google Scholar 

  30. Lefkowitz, R. J. (1998). G protein-coupled receptors. III. New roles for receptor kinases and beta-arrestins in receptor signaling and desensitization. Journal of Biological Chemistry, 273, 18677–18680.

    Article  PubMed  CAS  Google Scholar 

  31. Sorkin, A., & Von Zastrow, M. (2002). Signal transduction and endocytosis: Close encounters of many kinds. Nature Reviews Molecular Cell Biology, 3, 600–614.

    Article  PubMed  CAS  Google Scholar 

  32. Zastrow, O., Seidel, B., Kiess, W., Thiery, J., Keller, E., Bottner, A., et al. (2003). The soluble leptin receptor is crucial for leptin action: Evidence from clinical and experimental data. International Journal of Obesity and Related Metabolic Disorders, 27, 1472–1478.

    Article  PubMed  CAS  Google Scholar 

  33. Alwan, H. A., van Zoelen, E. J., & van Leeuwen, J. E. (2003). Ligand-induced lysosomal epidermal growth factor receptor (EGFR) degradation is preceded by proteasome-dependent EGFR de-ubiquitination. Journal of Biological Chemistry, 278, 35781–35790.

    Article  PubMed  CAS  Google Scholar 

  34. Berlin, I., Higginbotham, K. M., Dise, R. S., Sierra, M. I., & Nash, P. D. (2010). The deubiquitinating enzyme USP8 promotes trafficking and degradation of the chemokine receptor CXCR4 at the sorting endosome. Journal of Biological Chemistry, 285, 37895–37908.

    Article  PubMed  CAS  Google Scholar 

  35. Berlin, I., Schwartz, H., & Nash, P. D. (2010) Regulation of the epidermal growth factor receptor ubiquitination and trafficking by the USP8/STAM complex. Journal of Biological Chemistry, 285, 34909–34921.

    Article  PubMed  CAS  Google Scholar 

  36. de Melker, A. A., van der Horst, G., Calafat, J., Jansen, H., & Borst, J. (2001). c-Cbl ubiquitinates the EGF receptor at the plasma membrane and remains receptor associated throughout the endocytic route. Journal of Cell Science, 114, 2167–2178.

    PubMed  Google Scholar 

  37. Marchese, A., & Benovic, J. L. (2001). Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. Journal of Biological Chemistry, 276, 45509–45512.

    Article  PubMed  CAS  Google Scholar 

  38. Sierra, M. I., Wright, M. H., & Nash, P. D. (2010). AMSH interacts with ESCRT-0 to regulate the stability and trafficking of CXCR4. Journal of Biological Chemistry, 285, 13990–14004.

    Article  PubMed  CAS  Google Scholar 

  39. Fader, C. M., & Colombo, M. I. (2009). Autophagy and multivesicular bodies: Two closely related partners. Cell Death and Differentiation, 16, 70–78.

    Article  PubMed  CAS  Google Scholar 

  40. Im, Y. J., Wollert, T., Boura, E., & Hurley, J. H. (2009). Structure and function of the ESCRT-II-III interface in multivesicular body biogenesis. Developmental Cell, 17, 234–243.

    Article  PubMed  CAS  Google Scholar 

  41. Katzmann, D. J. (2006). No ESCRT to the melanosome: MVB sorting without ubiquitin. Developmental Cell, 10, 278–280.

    Article  PubMed  CAS  Google Scholar 

  42. Raiborg, C., & Stenmark, H. (2009). The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature, 458, 445–452.

    Article  PubMed  CAS  Google Scholar 

  43. Saksena, S., Sun, J., Chu, T., & Emr, S. D. (2007). ESCRTing proteins in the endocytic pathway. Trends in Biochemical Sciences, 32, 561–573.

    Article  PubMed  CAS  Google Scholar 

  44. McCullough, J., Row, P. E., Lorenzo, O., Doherty, M., Beynon, R., Clague, M. J., et al. (2006). Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM, a component of the multivesicular body-sorting machinery. Current Biology, 16, 160–165.

    Article  PubMed  CAS  Google Scholar 

  45. Row, P. E., Liu, H., Hayes, S., Welchman, R., Charalabous, P., Hofmann, K., et al. (2007). The MIT domain of UBPY constitutes a CHMP binding and endosomal localisation signal required for efficient EGF receptor degradation. Journal of Biological Chemistry, 282, 30929–30937.

    Article  PubMed  CAS  Google Scholar 

  46. Tsang, H. T., Connell, J. W., Brown, S. E., Thompson, A., Reid, E., & Sanderson, C. M. (2006). A systematic analysis of human CHMP protein interactions: Additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex. Genomics, 88, 333–346.

    Article  PubMed  CAS  Google Scholar 

  47. McCullough, J., Clague, M. J., & Urbe, S. (2004). AMSH is an endosome-associated ubiquitin isopeptidase. Journal of Cell Biology, 166, 487–492.

    Article  PubMed  CAS  Google Scholar 

  48. Jin, L., Williamson, A., Banerjee, S., Philipp, I., & Rape, M. (2008). Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell, 133, 653–665.

    Article  PubMed  CAS  Google Scholar 

  49. Kerscher, O., Felberbaum, R., & Hochstrasser, M. (2006). Modification of proteins by ubiquitin and ubiquitin-like proteins. Annual Review of Cell and Developmental Biology, 22, 159–180.

    Article  PubMed  CAS  Google Scholar 

  50. Komada, M. (2008). Controlling receptor downregulation by ubiquitination and deubiquitination. Current Drug Discovery Technologies, 5, 78–84.

    Article  PubMed  CAS  Google Scholar 

  51. Song, L., & Rape, M. (2008). Reverse the curse—the role of deubiquitination in cell cycle control. Current Opinion in Cell Biology, 20, 156–163.

    Article  PubMed  CAS  Google Scholar 

  52. Williams, R. L., & Urbe, S. (2007). The emerging shape of the ESCRT machinery. Nature Reviews Molecular Cell Biology, 8, 355–368.

    Article  PubMed  CAS  Google Scholar 

  53. Naviglio, S., Mattecucci, C., Matoskova, B., Nagase, T., Nomura, N., Di Fiore, P. P., et al. (1998). UBPY: A growth-regulated human ubiquitin isopeptidase. EMBO Journal, 17, 3241–3250.

    Article  PubMed  CAS  Google Scholar 

  54. Niendorf, S., Oksche, A., Kisser, A., Lohler, J., Prinz, M., Schorle, H., et al. (2007). Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo. Molecular and Cellular Biology, 27, 5029–5039.

    Article  PubMed  CAS  Google Scholar 

  55. Hasdemir, B., Murphy, J. E., Cottrell, G. S., & Bunnett, N. W. (2009). Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor 2. Journal of Biological Chemistry, 284, 28453–28466.

    Article  PubMed  CAS  Google Scholar 

  56. Hislop, J. N., Henry, A. G., Marchese, A., & von Zastrow, M. (2009). Ubiquitination regulates proteolytic processing of G protein-coupled receptors after their sorting to lysosomes. Journal of Biological Chemistry, 284, 19361–19370.

    Article  PubMed  CAS  Google Scholar 

  57. Alwan, H. A., & van Leeuwen, J. E. (2007). UBPY-mediated epidermal growth factor receptor (EGFR) de-ubiquitination promotes EGFR degradation. Journal of Biological Chemistry, 282, 1658–1669.

    Article  PubMed  CAS  Google Scholar 

  58. Sierra, M. I., Wright, M. H., & Nash, P. (2010). AMSH interacts with ESCRT-0 to regulate the stability and trafficking of CXCR4. Journal of Biological Chemistry, 285(18), 13990–14004.

    Article  PubMed  CAS  Google Scholar 

  59. Nakamura, M., Tanaka, N., Kitamura, N., & Komada, M. (2006). Clathrin anchors deubiquitinating enzymes, AMSH and AMSH-like protein, on early endosomes. Genes Cells, 11, 593–606.

    Article  PubMed  CAS  Google Scholar 

  60. Row, P. E., Prior, I. A., McCullough, J., Clague, M. J., & Urbe, S. (2006). The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation. Journal of Biological Chemistry, 281, 12618–12624.

    Article  PubMed  CAS  Google Scholar 

  61. Raiborg, C., Bache, K. G., Mehlum, A., Stang, E., & Stenmark, H. (2001). Hrs recruits clathrin to early endosomes. EMBO Journal, 20, 5008–5021.

    Article  PubMed  CAS  Google Scholar 

  62. Berry, D. M., Nash, P., Liu, S. K., Pawson, T., & McGlade, C. J. (2002). A high-affinity Arg-X-X-Lys SH3 binding motif confers specificity for the interaction between Gads and SLP-76 in T cell signaling. Current Biology, 12, 1336–1341.

    Article  PubMed  CAS  Google Scholar 

  63. Bjorkoy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., et al. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. Journal of Cell Biology, 171, 603–614.

    Article  PubMed  Google Scholar 

  64. Nixon, R. A., & Cataldo, A. M. (2006). Lysosomal system pathways: Genes to neurodegeneration in Alzheimer’s disease. J Alzheimers Dis, 9, 277–289.

    PubMed  CAS  Google Scholar 

  65. Mizuno, E., Kobayashi, K., Yamamoto, A., Kitamura, N., & Komada, M. (2006). A deubiquitinating enzyme UBPY regulates the level of protein ubiquitination on endosomes. Traffic, 7, 1017–1031.

    Article  PubMed  CAS  Google Scholar 

  66. Agromayor, M., & Martin-Serrano, J. (2006). Interaction of AMSH with ESCRT-III and deubiquitination of endosomal cargo. Journal of Biological Chemistry, 281, 23083–23091.

    Article  PubMed  CAS  Google Scholar 

  67. Lata, S., Roessle, M., Solomons, J., Jamin, M., Gottlinger, H. G., Svergun, D. I., et al. (2008). Structural basis for autoinhibition of ESCRT-III CHMP3. Journal of Molecular Biology, 378, 818–827.

    Article  PubMed  Google Scholar 

  68. Avvakumov, G. V., Walker, J. R., Xue, S., Finerty, P. J., Jr., Mackenzie, F., Newman, E. M., et al. (2006). Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8). Journal of Biological Chemistry, 281, 38061–38070.

    Article  PubMed  CAS  Google Scholar 

  69. Clague, M. J., & Urbe, S. (2006). Endocytosis: The DUB version. Trends in Cell Biology, 16, 551–559.

    Article  PubMed  CAS  Google Scholar 

  70. Carlton, J. G., & Martin-Serrano, J. (2007). Parallels between cytokinesis and retroviral budding: A role for the ESCRT machinery. Science, 316, 1908–1912.

    Article  PubMed  CAS  Google Scholar 

  71. Morita, E., Sandrin, V., Chung, H. Y., Morham, S. G., Gygi, S. P., Rodesch, C. K., et al. (2007). Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO Journal, 26, 4215–4227.

    Article  PubMed  CAS  Google Scholar 

  72. Mukai, A., Mizuno, E., Kobayashi, K., Matsumoto, M., Nakayama, K. I., Kitamura, N., et al. (2008). Dynamic regulation of ubiquitylation and deubiquitylation at the central spindle during cytokinesis. Journal of Cell Science, 121, 1325–1333.

    Article  PubMed  CAS  Google Scholar 

  73. Tanaka, N., Kaneko, K., Asao, H., Kasai, H., Endo, Y., Fujita, T., et al. (1999). Possible involvement of a novel STAM-associated molecule “AMSH” in intracellular signal transduction mediated by cytokines. Journal of Biological Chemistry, 274, 19129–19135.

    Article  PubMed  CAS  Google Scholar 

  74. Mizuno, E., Kitamura, N., & Komada, M. (2007). 14-3-3-dependent inhibition of the deubiquitinating activity of UBPY and its cancellation in the M phase. Experimental Cell Research, 313, 3624–3634.

    Article  PubMed  CAS  Google Scholar 

  75. Meijer, I. M., & van Leeuwen, J. E. (2011). ERBB2 is a target for USP8-mediated deubiquitination. Cellular Signalling, 23, 458–467.

    Article  PubMed  CAS  Google Scholar 

  76. Rusten, T. E., Filimonenko, M., Rodahl, L. M., Stenmark, H., & Simonsen, A. (2007). ESCRTing autophagic clearance of aggregating proteins. Autophagy, 2007, 4.

    Google Scholar 

  77. Levine, B., Sinha, S., & Kroemer, G. (2008). Bcl-2 family members: Dual regulators of apoptosis and autophagy. Autophagy, 4, 600–606.

    PubMed  CAS  Google Scholar 

  78. Filimonenko, M., Stuffers, S., Raiborg, C., Yamamoto, A., Malerod, L., Fisher, E. M., et al. (2007). Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. Journal of Cell Biology, 179, 485–500.

    Article  PubMed  CAS  Google Scholar 

  79. Lee, J. A., Beigneux, A., Ahmad, S. T., Young, S. G., & Gao, F. B. (2007). ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Current Biology, 17, 1561–1567.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 606737, USA

    Michelle H. Wright, Ilana Berlin & Piers D. Nash

  2. GCIS, 929 East 57th Street, Chicago, IL, 60637, USA

    Piers D. Nash

Authors
  1. Michelle H. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilana Berlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Piers D. Nash
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Piers D. Nash.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wright, M.H., Berlin, I. & Nash, P.D. Regulation of Endocytic Sorting by ESCRT–DUB-Mediated Deubiquitination. Cell Biochem Biophys 60, 39–46 (2011). https://doi.org/10.1007/s12013-011-9181-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-011-9181-9

Keywords

Search

Navigation