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Delivery of ubiquitinated substrates to protein-unfolding machines

Nature Cell Biology volume 7, pages 742–749 (2005)Cite this article

Abstract

Recent work has shown that ubiquitination leads to recognition of target proteins by diverse ubiquitin receptors. One family of receptors delivers the ubiquitinated proteins to the proteasome resulting in ATP-dependent substrate unfolding and proteolysis. A related family of ubiquitin-binding proteins seems to recruit ubiquitinated proteins to Cdc48, an ATPase ring complex that can also unfold proteins. Some targets seem to dock at Cdc48 before the proteasome does, in an ordered pathway. The intimate interplay between the proteasome and Cdc48, mediated in part by loosely associated ubiquitin receptors, has important functions in cellular regulation.

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Figure 1: Ubiquitin receptors of Saccharomyces cerevisiae and Homo sapiens.
Figure 2: Architecture of AAA complexes.
Figure 3: Proposed fate of ubiquitinated substrates of the proteasome and Cdc48.

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References

  1. Di Fiore, P. P., Polo, S. & Hofmann, K. When ubiquitin meets ubiquitin receptors: a signalling connection. Nature Rev. Mol. Cell Biol. 4, 491–497 (2003).

    Article  CAS  Google Scholar 

  2. Hicke, L. & Dunn, R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu. Rev. Cell. Dev. Biol. 19, 141–172 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Hicke, L., Schubert, H. L. & Hill, C. P. Ubiquitin-binding domains. Nature Rev. Mol. Cell. Biol. 6, 610–621 (2005).

    Article  CAS  Google Scholar 

  4. Deveraux, Q., Ustrell, V., Pickart, C. & Rechsteiner, M. A 26 S protease subunit that binds ubiquitin conjugates. J. Biol. Chem. 269, 7059–7061 (1994).

    CAS  PubMed  Google Scholar 

  5. van Nocker, S., Deveraux, Q., Rechsteiner, M. & Vierstra, R. D. Arabidopsis MBP1 gene encodes a conserved ubiquitin recognition component of the 26S proteasome. Proc. Natl Acad. Sci. USA 93, 856–860 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hartmann-Petersen, R. & Gordon, C. Protein degradation: recognition of ubiquitinylated substrates. Curr. Biol. 14, R754–R756 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Madura, K. Rad23 and Rpn10: perennial wallflowers join the melee. Trends Biochem. Sci. 29, 637–640 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Elsasser, S., Chandler-Militello, D., Muller, B., Hanna, J. & Finley, D. Rad23 and Rpn10 serve as alternative ubiquitin receptors for the proteasome. J. Biol. Chem. 279, 26817–26822 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Verma, R., Oania, R., Graumann, J. & Deshaies, R. J. Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell 118, 99–110 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Schauber, C. et al. Rad23 links DNA repair to the ubiquitin/proteasome pathway. Nature 391, 715–718 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Hiyama, H. et al. Interaction of hHR23 with S5a. The ubiquitin-like domain of hHR23 mediates interaction with S5a subunit of 26 S proteasome. J. Biol. Chem. 274, 28019–28025 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Wilkinson, C. R. et al. Proteins containing the UBA domain are able to bind to multi-ubiquitin chains. Nature Cell Biol. 3, 939–943 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Rao, H. & Sastry, A. Recognition of specific ubiquitin conjugates is important for the proteolytic functions of the ubiquitin-associated domain proteins Dsk2 and Rad23. J. Biol. Chem. 277, 11691–11695 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Elsasser, S. et al. Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nature Cell Biol. 4, 725–730 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Hofmann, K. & Bucher, P. The UBA domain: a sequence motif present in multiple enzyme classes of the ubiquitination pathway. Trends Biochem. Sci. 21, 172–173 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Lambertson, D., Chen, L. & Madura, K. Pleiotropic defects caused by loss of the proteasome-interacting factors Rad23 and Rpn10 of Saccharomyces cerevisiae. Genetics 153, 69–79 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen, L. & Madura, K. Rad23 promotes the targeting of proteolytic substrates to the proteasome. Mol. Cell. Biol. 22, 4902–4913 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Glockzin, S., Ogi, F. X., Hengstermann, A., Scheffner, M. & Blattner, C. Involvement of the DNA repair protein hHR23 in p53 degradation. Mol. Cell. Biol. 23, 8960–8969 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Buschhorn, B. A., Kostova, Z., Medicherla, B. & Wolf, D. H. A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins. FEBS Lett. 577, 422–426 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Richly, H. et al. A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120, 73–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Thrower, J. S., Hoffman, L., Rechsteiner, M. & Pickart, C. M. Recognition of the polyubiquitin proteolytic signal. EMBO J. 19, 94–102 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ortolan, T. G. et al. The DNA repair protein rad23 is a negative regulator of multi-ubiquitin chain assembly. Nature Cell Biol. 2, 601–608 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Kleijnen, M. F. et al. The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol. Cell 6, 409–419 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Raasi, S. & Pickart, C. M. Rad23 ubiquitin-associated domains (UBA) inhibit 26 S proteasome-catalyzed proteolysis by sequestering lysine 48-linked polyubiquitin chains. J. Biol. Chem. 278, 8951–8959 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Kim, I., Mi, K. & Rao, H. Multiple interactions of rad23 suggest a mechanism for ubiquitylated substrate delivery important in proteolysis. Mol. Biol. Cell 15, 3357–3365 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kamura, T. et al. Degradation of p57Kip2 mediated by SCFSkp2-dependent ubiquitylation. Proc. Natl Acad. Sci. USA 100, 10231–10236 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kamura, T. et al. Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase. Nature Cell Biol. 6, 1229–1235 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Kaplun, L. et al. The DNA damage inducible UbL–UbA protein Ddi1 participates in Mec1-mediated degradation of Ho endonuclease. Mol. Cell. Biol. 25, 5355–5362 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sakata, E. et al. Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain. EMBO Rep. 4, 301–306 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hartmann-Petersen, R., Hendil, K. B. & Gordon, C. Ubiquitin binding proteins protect ubiquitin conjugates from disassembly. FEBS Lett. 535, 77–81 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Hofmann, K. & Falquet, L. A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Trends Biochem. Sci. 26, 347–350 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Young, P., Deveraux, Q., Beal, R. E., Pickart, C. M. & Rechsteiner, M. Characterization of two polyubiquitin binding sites in the 26 S protease subunit 5a. J. Biol. Chem. 273, 5461–5467 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Fisher, R. D. et al. Structure and ubiquitin binding of the ubiquitin-interacting motif. J. Biol. Chem. 278, 28976–28984 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Mueller, T. D. & Feigon, J. Structural determinants for the binding of ubiquitin-like domains to the proteasome. EMBO J. 22, 4634–4645 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fujiwara, K. et al. Structure of the ubiquitin-interacting motif of S5a bound to the ubiquitin-like domain of HR23B. J. Biol. Chem. 279, 4760–4767 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Kawahara, H. et al. Developmentally regulated, alternative splicing of the Rpn10 gene generates multiple forms of 26S proteasomes. EMBO J. 19, 4144–4153 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang, Q., Young, P. & Walters, K. J. Structure of S5a bound to monoubiquitin provides a model for polyubiquitin recognition. J. Mol. Biol. 348, 727–739 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Walters, K. J., Lech, P. J., Goh, A. M., Wang, Q. & Howley, P. M. DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a. Proc. Natl Acad. Sci. USA 100, 12694–12699 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Saeki, Y., Sone, T., Toh-e, A. & Yokosawa, H. Identification of ubiquitin-like protein-binding subunits of the 26S proteasome. Biochem. Biophys. Res. Commun. 296, 813–819 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Stone, M. et al. Uch2/Uch37 is the major deubiquitinating enzyme associated with the 26S proteasome in fission yeast. J. Mol. Biol. 344, 697–706 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Schauber, C., Chen, L., Tongaonkar, P., Vega, I. & Madura, K. Sequence elements that contribute to the degradation of yeast G alpha. Genes Cells 3, 307–319 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Funakoshi, M., Sasaki, T., Nishimoto, T. & Kobayashi, H. Budding yeast Dsk2p is a polyubiquitin-binding protein that can interact with the proteasome. Proc. Natl Acad. Sci. USA 99, 745–750 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Saeki, Y., Saitoh, A., Toh-e, A. & Yokosawa, H. Ubiquitin-like proteins and Rpn10 play cooperative roles in ubiquitin-dependent proteolysis. Biochem. Biophys. Res. Commun. 293, 986–992 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Bertolaet, B. L. et al. UBA domains of DNA damage-inducible proteins interact with ubiquitin. Nature Struct. Biol. 8, 417–422 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Lam, Y. A., Lawson, T. G., Velayutham, M., Zweier, J. L. & Pickart, C. M. A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal. Nature 416, 763–767 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Chuang, S. M. et al. Proteasome-mediated degradation of cotranslationally damaged proteins involves translation elongation factor 1A. Mol. Cell. Biol. 25, 403–413 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Varadan, R. et al. Solution conformation of Lys63-linked di-ubiquitin chain provides clues to functional diversity of polyubiquitin signaling. J. Biol. Chem. 279, 7055–7063 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Raasi, S., Orlov, I., Fleming, K. G. & Pickart, C. M. Binding of polyubiquitin chains to ubiquitin-associated (UBA) domains of HHR23A. J. Mol. Biol. 341, 1367–1379 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Janse, D. M., Crosas, B., Finley, D. & Church, G. M. Localization to the proteasome is sufficient for degradation. J. Biol. Chem. 279, 21415–21420 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Meyer, H. H., Wang, Y. & Warren, G. Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes, p47 and Ufd1-Npl4. EMBO J. 21, 5645–5652 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ye, Y., Meyer, H. H. & Rapoport, T. A. Function of the p97–Ufd1–Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J. Cell Biol. 162, 71–84 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schuberth, C., Richly, H., Rumpf, S. & Buchberger, A. Shp1 and Ubx2 are adaptors of Cdc48 involved in ubiquitin-dependent protein degradation. EMBO Rep. 5, 818–824 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hartmann-Petersen, R. et al. The Ubx2 and Ubx3 cofactors direct Cdc48 activity to proteolytic and nonproteolytic ubiquitin-dependent processes. Curr. Biol. 14, 824–828 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Buchberger, A., Howard, M. J., Proctor, M. & Bycroft, M. The UBX domain: a widespread ubiquitin-like module. J. Mol. Biol. 307, 17–24 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Woodman, P. G. p97, a protein coping with multiple identities. J. Cell Sci. 116, 4283–4290 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Meyer, H. H., Shorter, J. G., Seemann, J., Pappin, D. & Warren, G. A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J. 19, 2181–2192 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dreveny, I. et al. Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47. EMBO J. 23, 1030–1039 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Iyer, L. M., Leipe, D. D., Koonin, E. V. & Aravind, L. Evolutionary history and higher order classification of AAA+ ATPases. J. Struct. Biol. 146, 11–31 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Alam, S. L. et al. Ubiquitin interactions of NZF zinc fingers. EMBO J. 23, 1411–1421 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bruderer, R. M., Brasseur, C. & Meyer, H. H. The AAA ATPase p97/VCP interacts with its alternative co-factors, Ufd1-Npl4 and p47, through a common bipartite binding mechanism. J. Biol. Chem. 279, 49609–49616 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Decottignies, A., Evain, A. & Ghislain, M. Binding of Cdc48p to a ubiquitin-related UBX domain from novel yeast proteins involved in intracellular proteolysis and sporulation. Yeast 21, 127–139 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Pickart, C. M. & Cohen, R. E. Proteasomes and their kin: proteases in the machine age. Nature Rev. Mol. Cell Biol. 5, 177–187 (2004).

    Article  CAS  Google Scholar 

  63. Muratani, M. & Tansey, W. P. How the ubiquitin-proteasome system controls transcription. Nature Rev. Mol. Cell Biol. 4, 192–201 (2003).

    Article  CAS  Google Scholar 

  64. Tsai, B., Ye, Y. & Rapoport, T. A. Retro-translocation of proteins from the endoplasmic reticulum into the cytosol. Nature Rev. Mol. Cell Biol. 3, 246–255 (2002).

    Article  CAS  Google Scholar 

  65. Bays, N. W. & Hampton, R. Y. Cdc48–Ufd1–Npl4: stuck in the middle with Ub. Curr. Biol. 12, R366–R371 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Ghislain, M., Dohmen, R. J., Levy, F. & Varshavsky, A. Cdc48p interacts with Ufd3p, a WD repeat protein required for ubiquitin-mediated proteolysis in Saccharomyces cerevisiae. EMBO J. 15, 4884–4899 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cao, K., Nakajima, R., Meyer, H. H. & Zheng, Y. The AAA-ATPase Cdc48/p97 regulates spindle disassembly at the end of mitosis. Cell 115, 355–367 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Fu, X., Ng, C., Feng, D. & Liang, C. Cdc48p is required for the cell cycle commitment point at Start via degradation of the G1–CDK inhibitor Far1p. J. Cell Biol. 163, 21–26 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bays, N. W., Wilhovsky, S. K., Goradia, A., Hodgkiss-Harlow, K. & Hampton, R. Y. HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol. Biol. Cell 12, 4114–4128 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Braun, S., Matuschewski, K., Rape, M., Thoms, S. & Jentsch, S. Role of the ubiquitin-selective CDC48(UFD1/NPL4)chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J. 21, 615–621 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jarosch, E. et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nature Cell Biol. 4, 134–139 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Rabinovich, E., Kerem, A., Frohlich, K. U., Diamant, N. & Bar-Nun, S. AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol. Cell. Biol. 22, 626–634 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ye, Y., Meyer, H. H. & Rapoport, T. A. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414, 652–656 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Glickman, M. H. et al. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell 94, 615–623 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Rape, M. et al. Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107, 667–677 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Hitchcock, A. L. et al. The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation. Mol. Biol. Cell 12, 3226–3241 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang, Y., Satoh, A., Warren, G. & Meyer, H. H. VCIP135 acts as a deubiquitinating enzyme during p97-p47-mediated reassembly of mitotic Golgi fragments. J Cell Biol 164, 973–978 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. DeLaBarre, B. & Brunger, A. T. Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nature Struct. Biol. 10, 856–863 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Huyton, T. et al. The crystal structure of murine p97/VCP at 3.6A. J. Struct. Biol. 144, 337–348 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Zhang, X. et al. Structure of the AAA ATPase p97. Mol. Cell 6, 1473–1484 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Weibezahn, J. et al. Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB. Cell 119, 653–665 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Uchiyama, K. et al. VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is required for Golgi and ER assembly in vivo. J. Cell Biol. 159, 855–866 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ho, Y. et al. Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415, 180–183 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Koegl, M. et al. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96, 635–644 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Dai, R. M. & Li, C. C. Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nature Cell Biol. 3, 740–744 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Zhong, X. et al. AAA ATPase p97/valosin-containing protein interacts with gp78, a ubiquitin ligase for endoplasmic reticulum-associated degradation. J. Biol. Chem. 279, 45676–45684 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Xie, Y. & Varshavsky, A. Physical association of ubiquitin ligases and the 26S proteasome. Proc. Natl Acad. Sci. USA 97, 2497–2502 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Verma, R. et al. Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol. Biol. Cell 11, 3425–3439 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Leggett, D. S. et al. Multiple associated proteins regulate proteasome structure and function. Mol. Cell 10, 495–507 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Whiteheart, S. W. & Matveeva, E. A. Multiple binding proteins suggest diverse functions for the N-ethylmaleimide sensitive factor. J. Struct. Biol. 146, 32–43 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Schnell, J. D. & Hicke, L. Non-traditional functions of ubiquitin and ubiquitin-binding proteins. J. Biol. Chem. 278, 35857–35860 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Kanayama, A. et al. TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains. Mol. Cell 15, 535–548 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Helliwell, S. B., Losko, S. & Kaiser, C. A. Components of a ubiquitin ligase complex specify polyubiquitination and intracellular trafficking of the general amino acid permease. J. Cell Biol. 153, 649–662 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kamitani, T., Kito, K., Fukuda-Kamitani, T. & Yeh, E. T. Targeting of NEDD8 and its conjugates for proteasomal degradation by NUB1. J. Biol. Chem. 276, 46655–46660 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Tanaka, T., Kawashima, H., Yeh, E. T. & Kamitani, T. Regulation of the NEDD8 conjugation system by a splicing variant, NUB1L. J. Biol. Chem. 278, 32905–32913 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Y. Ye, H. Meyer and many other colleagues for comments on the manuscript, and apologize that due to space constraints we have been unable to cite all papers relevant to the development of this field.

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    Suzanne Elsasser & Daniel Finley

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Elsasser, S., Finley, D. Delivery of ubiquitinated substrates to protein-unfolding machines. Nat Cell Biol 7, 742–749 (2005). https://doi.org/10.1038/ncb0805-742

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