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Regulatory functions of ubiquitination in the immune system
Nature Immunologyvolume 3, pages20–26 (2002)Cite this article
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Abstract
Protein modificationvia covalent attachment of ubiquitin has emerged as one of the most common regulatory processes in all eukaryotes; it is possibly second only to phosphorylation. In fact, ubiquitination and phosphorylation have much in common: both occur rapidly—often in response to an extracellular signal—and both are quickly reversed by a large set of dedicated enzymes termed deubiquitination enzymes and phosphatases, respectively. In addition, these two protein-modification events often cooperate in mobilizing a particular cellular pathway. Traditionally, ubiquitination has been associated with proteolytic events, mostly in conjunction with the 26S proteosome. Recently, however, ubiquitination has been implicated in other regulatory mechanisms. Some involve proteosome-independent protein degradation, whereas others are entirely proteolysis-independent, ranging from protein kinase activation to translation control. Therefore, it is not surprising that the ever-evolving immune system is an excellent mirror for the multiple roles played by ubiquitination within an organism.
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References
Hershko, A., Ciechanover, A. & Varshavsky, A. Basic Medical Research Award. The ubiquitin system.Nature Med.6, 1073–1081 (2000).
Ciechanover, A., Orian, A. & Schwartz, A. L. Ubiquitin-mediated proteolysis: biological regulationvia destruction.Bioessays22, 442–451 (2000).
Hochstrasser, M. Evolution and function of ubiquitin-like protein-conjugation systems.Nature Cell. Biol.2, 153–157 (2000).
Jentsch, S. & Pyrowolakis, G. Ubiquitin and its kin: how close are the family ties?Trends Cell Biol.10, 335–342 (2000).
Read, M. A. et al. Nedd8 modification of cul-1 activates SCFβ–TrCP -dependent ubiquitination of IκBα.Mol. Cell. Biol.20, 2326–2333 (2000).
Kawakami, T. et al. NEDD8 recruits E2-ubiquitin to SCF E3 ligase.EMBO J.20, 4003–4012 (2001).
Hay, R. T. Protein modification by SUMO.Trends Biochem. Sci.26, 332–333 (2001).
Mahajan, R., Delphin, C., Guan, T., Gerace, L. & Melchior, F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2.Cell88, 97–107 (1997).
Jackson, P. K. et al. The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases.Trends Cell Biol.10, 429–439 (2000).
Weissman, A. M. Themes and variations on ubiquitylation.Nature Rev. Mol. Cell. Biol.2, 169–178 (2001).
Deshaies, R. J. SCF and Cullin/Ring H2-based ubiquitin ligases.Annu. Rev. Cell. Dev. Biol.15, 435–467 (1999).
Zachariae, W. & Nasmyth, K. Whose end is destruction: cell division and the anaphase-promoting complex.Genes Dev.13, 2039–2058 (1999).
Kondo, K. & Kaelin, W. G. Jr The von Hippel-Lindau tumor suppressor gene.Exp. Cell. Res.264, 117–125 (2001).
Hatakeyama, S., Yada, M., Matsumoto, M., Ishida, N. & Nakayama, K. I. U box proteins as a new family of ubiquitin-protein ligases.J. Biol. Chem.276, 33111–33120 (2001).
Yewdell, J. W. Not such a dismal science: the economics of protein synthesis, folding, degradation and antigen processing.Trends Cell Biol.11, 294–297 (2001).
Kloetzel, P. M. Antigen processing by the proteasome.Nature Rev. Mol. Cell. Biol.2, 179–187 (2001).
Baeuerle, P. A. & Baltimore, D. NF-κB: ten years after.Cell87, 13–20 (1996).
Ghosh, S., May, M. J. & Kopp, E. B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses.Annu. Rev. Immunol.16, 225–260 (1998).
Baldwin, A. S. Jr Series introduction: the transcription factor NF-κB and human disease.J. Clin. Invest.107, 3–6 (2001).
Silverman, N. & Maniatis, T. NF-κB signaling pathways in mammalian and insect innate immunity.Genes Dev.15, 2321–2342 (2001).
Sha, W. C., Liou, H. C., Tuomanen, E. I. & Baltimore, D. Targeted disruption of the p50 subunit of NF-κB B leads to multifocal defects in immune responses.Cell80, 321–330 (1995).
Ishikawa, H. et al. Chronic inflammation and susceptibility to bacterial infections in mice lacking the polypeptide (p)105 precursor NF-κB but expressing p50.J. Exp. Med.187, 985–996 (1998).
Lavon, I. et al. High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-κB activation.Nature Med.6, 573–577 (2000).
Mansour, S. et al. Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection.Am. J. Med. Genet.99, 172–177 (2001).
Boothby, M. R., Mora, A. L., Scherer, D. C., Brockman, J. A. & Ballard, D. W. Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor NF-κB.J. Exp. Med.185, 1897–1907 (1997).
Hettmann, T., DiDonato, J., Karin, M. & Leiden, J. M. An essential role for NF-κB in promoting double positive thymocyte apoptosis.J. Exp. Med.189, 145–158 (1999).
Grossmann, M. et al. The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression.EMBO J.19, 6351–6360 (2000).
Voll, R. E. et al. NF-κB activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development.Immunity13, 677–689 (2000).
Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity.Annu. Rev. Immunol.18, 621–663 (2000).
Yaron, A. et al. Identification of the receptor component of the IκBα-ubiquitin ligase.Nature396, 590–594 (1998).
Winston, J. T. et al. The SCF β-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitinationin vitro.Genes Dev.13, 270–283 (1999).
Spencer, E., Jiang, J. & Chen, Z. J. Signal-induced ubiquitination of IκBα by the F-box protein Slimb/β-TrCP.Genes Dev.13, 284–294 (1999).
Hattori, K., Hatakeyama, S., Shirane, M., Matsumoto, M. & Nakayama, K. Molecular dissection of the interactions among pIκBα, FWD1, and Skp1 required for ubiquitin-mediated proteolysis of pIκBα.J. Biol. Chem.274, 29641–29647 (1999).
Kroll, M. et al. Inducible degradation of pIκBα by the proteasome requires interaction with the F-box protein h-β-TrCP.J. Biol. Chem.274, 7941–7945 (1999).
Yaron, A. et al. Inhibition of NF-κB cellular functionvia specific targeting of the IκB-ubiquitin ligase.EMBO J.16, 6486–6494 (1997).
Arenzana-Seisdedos, F. et al. Nuclear localization of IκBα promotes active transport of NF-κB from the nucleus to the cytoplasm.J. Cell Sci.110, 369–378 (1997).
Huang, T. T., Kudo, N., Yoshida, M. & Miyamoto, S. A nuclear export signal in the N-terminal regulatory domain of pIκBα controls cytoplasmic localization of inactive NF-κB/IκBα complexes.Proc. Natl Acad. Sci. USA97, 1014–1019 (2000).
Johnson, C., Van Antwerp, D. & Hope, T. J. An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of pIκBα.EMBO J.18, 6682–6693 (1999).
Malek, S., Chen, Y., Huxford, T. & Ghosh, G. IκBβ, but not pIκBα, functions as a classical cytoplasmic inhibitor of NF-κB dimers by masking both NF-κB nuclear localization sequences in resting cells.J. Biol. Chem.276, 45225–45235 (2001).
Tam, W. F. & Sen, R. IκB family members function by different mechanisms.J. Biol. Chem.276, 7701–7704 (2001).
Wilkinson, K. D. Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome.Semin. Cell. Dev. Biol.11, 141–148 (2000).
Neish, A. S. et al. Prokaryotic regulation of epithelial responses by inhibition of pIκBα ubiquitination.Science289, 1560–1503 (2000).
Lin, L., DeMartino, G. N. & Greene, W. C. Cotranslational biogenesis of NF-κB p50 by the 26S proteasome.Cell92, 819–828 (1998).
Ciechanover, A. et al. Mechanisms of ubiquitin-mediated, limited processing of the NF-κB1 precursor protein p105.Biochimie83, 341–349 (2001).
Orian, A. et al. SCFβ–TrCP ubiquitin ligase-mediated processing of NF-κB p105 requires phosphorylation of its C-terminus by IκB kinase.EMBO J.19, 2580–2591 (2000).
Heissmeyer, V., Krappmann, D., Hatada, E. N. & Scheidereit, C. Shared pathways of IκB kinase-induced SCFβ–TrC-mediated ubiquitination and degradation for the NF-κB precursor p105 and pIκBα.Mol. Cell. Biol.21, 1024–1035 (2001).
Orian, A. et al. Structural motifs involved in ubiquitin-mediated processing of the NF-κB precursor p105: roles of the glycine-rich region and a downstream ubiquitination domain.Mol. Cell. Biol.19, 3664–3673 (1999).
Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway.Science293, 1495–1499 (2001).
Lin, L. & Ghosh, S. A glycine-rich region in NF-κB p105 functions as a processing signal for the generation of the p50 subunit.Mol. Cell. Biol.16, 2248–22454 (1996).
Levitskaya, J., Sharipo, A., Leonchiks, A., Ciechanover, A. & Masucci, M. G. Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1.Proc. Natl Acad. Sci. USA94, 12616–12621 (1997).
Hoppe, T. et al. Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing.Cell102, 577–586 (2000).
Sears, C., Olesen, J., Rubin, D., Finley, D. & Maniatis, T. NF-κB p105 processingvia the ubiquitin-proteasome pathway.J. Biol. Chem.273, 1409–1419 (1998).
Silverman, N. et al. ADrosophila IκB kinase complex required for Relish cleavage and antibacterial immunity.Genes Dev.14, 2461–2471 (2000).
Stoven, S., Ando, I., Kadalayil, L., Engstrom, Y. & Hultmark, D. Activation of theDrosophila NF-κB factor Relish by rapid endoproteolytic cleavage.EMBO Rep.1, 347–352 (2000).
Leulier, F., Rodriguez, A., Khush, R. S., Abrams, J. M. & Lemaitre, B. TheDrosophila caspase Dredd is required to resist gram-negative bacterial infection.EMBO Rep.1, 353–358 (2000).
O'Neill, L. A. & Dinarello, C. A. The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense.Immunol. Today21, 206–209 (2000).
Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain.Cell103, 351–361 (2000).
Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK.Nature412, 346–351 (2001).
Hofmann, R. M. & Pickart, C. M. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair.Cell96, 645–653 (1999).
Takayanagi, H. et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross- talk between RANKL and IFN-γ.Nature408, 600–605 (2000).
Yamaguchi, K. et al. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway.EMBO J.18, 179–187 (1999).
Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M. & Ashwell, J. D. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli.Science288, 874–877 (2000).
Chen, Z. J., Parent, L. & Maniatis, T. Site-specific phosphorylation of pIκBα by a novel ubiquitination- dependent protein kinase activity.Cell84, 853–862 (1996).
Pawson, T. & Nash, P. Protein-protein interactions define specificity in signal transduction.Genes Dev.14, 1027–1047 (2000).
Hicke, L. A new ticket for entry into budding vesicles-ubiquitin.Cell106, 527–530 (2001).
Katzmann, D. J., Babst, M. & Emr, S. D. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I.Cell106, 145–155 (2001).
Rocca, A., Lamaze, C., Subtil, A. & Dautry-Varsat, A. Involvement of the ubiquitin/proteasome system in sorting of the interleukin 2 receptor β chain to late endocytic compartments.Mol. Biol. Cell.12, 1293–1301 (2001).
Thien, C. B. & Langdon, W. Y. Cbl: many adaptations to regulate protein tyrosine kinases.Nature Rev. Mol. Cell. Biol.2, 294–307 (2001).
Yoon, C. H., Lee, J., Jongeward, G. D. & Sternberg, P. W. Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl.Science269, 1102–1105 (1995).
Ota, Y. & Samelson, L. E. The product of the proto-oncogene c-cbl: a negative regulator of the Syk tyrosine kinase.Science276, 418–420 (1997).
Levkowitz, G. et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1.Mol. Cell.4, 1029–1040 (1999).
Joazeiro, C. A. et al. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2- dependent ubiquitin-protein ligase.Science286, 309–312 (1999).
Lee, P. S. et al. The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation.EMBO J.18, 3616–3628 (1999).
Fang, D. & Liu, Y. C. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells.Nature Immunol.2, 870–875 (2001).
Rudd, C. E. & Schneider, H. Lymphocyte signaling: Cbl sets the threshold for autoimmunity.Curr. Biol.10, R344–347 (2000).
Chiang, Y. J. et al. Cbl-b regulates the CD28 dependence of T-cell activation.Nature403, 216–220 (2000).
Krawczyk, C. et al. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells.Immunity13, 463–473 (2000).
Krawczyk, C. & Penninger, J. M. Molecular controls of antigen receptor clustering and autoimmunity.Trends Cell Biol.11, 212–220 (2001).
Fang, D. et al. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3- kinase for ubiquitination in T cells.J. Biol. Chem.276, 4872–4878 (2001).
D'Andrea, A. & Pellman, D. Deubiquitinating enzymes: a new class of biological regulators.Crit. Rev. Biochem. Mol. Biol.33, 337–352 (1998).
Migone, T. S. et al. The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal.Blood98, 1935–1941 (2001).
Yasukawa, H., Sasaki, A. & Yoshimura, A. Negative regulation of cytokine signaling pathways.Annu. Rev. Immunol.18, 143–164 (2000).
Sporri, B., Kovanen, P. E., Sasaki, A., Yoshimura, A. & Leonard, W. J. JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling.Blood97, 221–226 (2001).
Krebs, D. L. & Hilton, D. J. Socs proteins: negative regulators of cytokine signaling.Stem Cells19, 378–387 (2001).
De Sepulveda, P., Ilangumaran, S. & Rottapel, R. Suppressor of cytokine signaling-1 inhibits VAV function through protein degradation.J. Biol. Chem.275, 14005–14008 (2000).
Nash, P. et al. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication.Nature414, 514–521 (2001).
Acknowledgements
I thank members of my laboratory, A. Ciechanover and A. Mahler for helpful comments on the manuscript. Supported by the Israel Science Foundation; funded by the Israel Academy for Sciences and Humanities-Centers of Excellence Program, the German-Israeli Program (DIP) and the European Community (5th Framework).
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The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel
Yinon Ben-Neriah
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Ben-Neriah, Y. Regulatory functions of ubiquitination in the immune system.Nat Immunol3, 20–26 (2002). https://doi.org/10.1038/ni0102-20
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