Abstract
Ubiquitination is crucial for a plethora of physiological processes, including cell survival and differentiation and innate and adaptive immunity. In recent years, considerable progress has been made in the understanding of the molecular action of ubiquitin in signaling pathways and how alterations in the ubiquitin system lead to the development of distinct human diseases. Here we describe the role of ubiquitination in the onset and progression of cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infection and muscle dystrophies. Moreover, we indicate how current knowledge could be exploited for the development of new clinical therapies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).
Grabbe, C., Husnjak, K. & Dikic, I. The spatial and temporal organization of ubiquitin networks. Nat. Rev. Mol. Cell Biol. 12, 295–307 (2011).
Schwartz, A.L. & Ciechanover, A. Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu. Rev. Pharmacol. Toxicol. 49, 73–96 (2009).
Hoeller, D. & Dikic, I. Targeting the ubiquitin system in cancer therapy. Nature 458, 438–444 (2009).
Richardson, P.G. et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 348, 2609–2617 (2003).
Hideshima, T. et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 61, 3071–3076 (2001).
Lipkowitz, S. & Weissman, A.M. RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat. Rev. Cancer 11, 629–643 (2011).
Kirkin, V. & Dikic, I. Ubiquitin networks in cancer. Curr. Opin. Genet. Dev. 21, 21–28 (2011).
Wade, M., Li, Y.C. & Wahl, G.M. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat. Rev. Cancer 13, 83–96 (2013).
Frescas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nat. Rev. Cancer 8, 438–449 (2008).
Sheaff, R.J., Groudine, M., Gordon, M., Roberts, J.M. & Clurman, B.E. Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev. 11, 1464–1478 (1997).
Schmidt, M.H. & Dikic, I. The Cbl interactome and its functions. Nat. Rev. Mol. Cell Biol. 6, 907–918 (2005).
Gnarra, J.R. et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat. Genet. 7, 85–90 (1994).
Kanno, H. et al. Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res. 54, 4845–4847 (1994).
Maxwell, P.H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).
Reyes-Turcu, F.E., Ventii, K.H. & Wilkinson, K.D. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu. Rev. Biochem. 78, 363–397 (2009).
Hymowitz, S.G. & Wertz, I.E. A20: from ubiquitin editing to tumour suppression. Nat. Rev. Cancer 10, 332–341 (2010).
Bignell, G.R. et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nat. Genet. 25, 160–165 (2000).
Dey, A. et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337, 1541–1546 (2012).
Sasaki, A.T. et al. Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors. Sci. Signal. 4, ra13 (2011).
Williams, S.A. et al. USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Cell 146, 918–930 (2011).
Pereg, Y. et al. Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A. Nat. Cell Biol. 12, 400–406 (2010).
Massoumi, R. CYLD: a deubiquitination enzyme with multiple roles in cancer. Future Oncol. 7, 285–297 (2011).
Bonnet, M. & Courtois, G. CYLD deubiquitinase as a recurrent target in oncogenic processes. Med. Sci. (Paris) 27, 626–631 (2011) [transl].
Xu, L., Lubkov, V., Taylor, L.J. & Bar-Sagi, D. Feedback regulation of Ras signaling by Rabex-5–mediated ubiquitination. Curr. Biol. 20, 1372–1377 (2010).
Kim, S.E. et al. H-Ras is degraded by Wnt/β-catenin signaling via β-TrCP-mediated polyubiquitylation. J. Cell Sci. 122, 842–848 (2009).
Baker, R. et al. Site-specific monoubiquitination activates Ras by impeding GTPase-activating protein function. Nat. Struct. Mol. Biol. 20, 46–52 (2013).
Sasaki, A.T. et al. Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors. Sci. Signal. 4, ra13 (2011).
Luo, J.L., Kamata, H. & Karin, M. IKK/NF-κB signaling: balancing life and death—a new approach to cancer therapy. J. Clin. Invest. 115, 2625–2632 (2005).
Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol. 12, 715–723 (2011).
Vucic, D., Dixit, V.M. & Wertz, I.E. Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat. Rev. Mol. Cell Biol. 12, 439–452 (2011).
Keats, J.J. et al. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell 12, 131–144 (2007).
Annunziata, C.M. et al. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12, 115–130 (2007).
Demchenko, Y.N. et al. Classical and/or alternative NF-κB pathway activation in multiple myeloma. Blood 115, 3541–3552 (2010).
Pelzer, C. et al. The protease activity of the paracaspase MALT1 is controlled by monoubiquitination. Nat. Immunol. 14, 337–345 (2013).
Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131, 669–681 (2007).
Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006).
Kottemann, M.C. & Smogorzewska, A. Fanconi anaemia and the repair of Watson and Crick DNA crosslinks. Nature 493, 356–363 (2013).
Knipscheer, P. et al. The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science 326, 1698–1701 (2009).
Garcia-Higuera, I. et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol. Cell 7, 249–262 (2001).
Liu, T., Ghosal, G., Yuan, J., Chen, J. & Huang, J. FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science 329, 693–696 (2010).
Lehmann, A.R. DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Biochimie 85, 1101–1111 (2003).
Keeney, S., Chang, G.J. & Linn, S. Characterization of a human DNA damage binding protein implicated in xeroderma pigmentosum E. J. Biol. Chem. 268, 21293–21300 (1993).
Mattiroli, F. et al. RNF168 ubiquitinates K13–15 on H2A/H2AX to drive DNA damage signaling. Cell 150, 1182–1195 (2012).
Fradet-Turcotte, A. et al. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499, 50–54 (2013).
Sharma, N. et al. USP3 counteracts RNF168 via deubiquitinating H2A and γH2AX at lysine 13 and 15. Cell Cycle 13, 106–114 (2014).
Mosbech, A., Lukas, C., Bekker-Jensen, S. & Mailand, N. The deubiquitylating enzyme USP44 counteracts the DNA double-strand break response mediated by the RNF8 and RNF168 ubiquitin ligases. J. Biol. Chem. 288, 16579–16587 (2013).
Masuda, Y. & Kamiya, K. Molecular nature of radiation injury and DNA repair disorders associated with radiosensitivity. Int. J. Hematol. 95, 239–245 (2012).
Stewart, G.S. et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136, 420–434 (2009).
Blundred, R.M. & Stewart, G.S. DNA double-strand break repair, immunodeficiency and the RIDDLE syndrome. Expert Rev. Clin. Immunol. 7, 169–185 (2011).
Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).
Mariño, G. et al. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J. Biol. Chem. 282, 18573–18583 (2007).
Takamura, A. et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795–800 (2011).
Takahashi, Y. et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat. Cell Biol. 9, 1142–1151 (2007).
Kim, M.S. et al. Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite instability. Hum. Pathol. 39, 1059–1063 (2008).
White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer 12, 401–410 (2012).
Hashimoto, D. et al. Autophagy is needed for the growth of pancreatic adenocarcinoma and has a cytoprotective effect against anticancer drugs. Eur. J. Cancer 50, 1382–1390 (2014).
Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Disc. 4, 905–913 (2014).
Guo, J.Y. et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25, 460–470 (2011).
Lock, R. et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol. Biol. Cell 22, 165–178 (2011).
Guo, J.Y. et al. Autophagy suppresses progression of K-ras–induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev. 27, 1447–1461 (2013).
Rosenfeldt, M.T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013).
Aradhya, S. et al. Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-γ). Am. J. Hum. Genet. 68, 765–771 (2001).
Aradhya, S. et al. A recurrent deletion in the ubiquitously expressed NEMO (IKK-γ) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum. Mol. Genet. 10, 2171–2179 (2001).
Courtois, G. & Israel, A. IKK regulation and human genetics. Curr. Top. Microbiol. Immunol. 349, 73–95 (2011).
Bustamante, J., Picard, C., Boisson-Dupuis, S., Abel, L. & Casanova, J.L. Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann. NY Acad. Sci. 1246, 92–101 (2011).
Rahighi, S. et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 136, 1098–1109 (2009).
Seymour, R.E. et al. Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun. 8, 416–421 (2007).
Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13, 1178–1186 (2012).
Pachlopnik Schmid, J. et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 117, 1522–1529 (2011).
Marsh, R.A. et al. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood 116, 1079–1082 (2010).
Damgaard, R.B. et al. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol. Cell 46, 746–758 (2012).
Corn, J.E. & Vucic, D. Ubiquitin in inflammation: the right linkage makes all the difference. Nat. Struct. Mol. Biol. 21, 297–300 (2014).
Bennett, E.J., Bence, N.F., Jayakumar, R. & Kopito, R.R. Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol. Cell 17, 351–365 (2005).
Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
Lam, Y.A. et al. Inhibition of the ubiquitin-proteasome system in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 97, 9902–9906 (2000).
Tofaris, G.K., Razzaq, A., Ghetti, B., Lilley, K.S. & Spillantini, M.G. Ubiquitination of α-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J. Biol. Chem. 278, 44405–44411 (2003).
Anderson, J.P. et al. Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281, 29739–29752 (2006).
Rott, R. et al. Monoubiquitylation of α-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. J. Biol. Chem. 283, 3316–3328 (2008).
Lee, J.T., Wheeler, T.C., Li, L. & Chin, L.S. Ubiquitination of α-synuclein by Siah-1 promotes α-synuclein aggregation and apoptotic cell death. Hum. Mol. Genet. 17, 906–917 (2008).
Meier, F. et al. Semisynthetic, site-specific ubiquitin modification of α-synuclein reveals differential effects on aggregation. J. Am. Chem. Soc. 134, 5468–5471 (2012).
Spratt, D.E. et al. A molecular explanation for the recessive nature of parkin-linked Parkinson's disease. Nat. Commun. 4, 1983 (2013).
Chen, Y. & Dorn, G.W. II. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340, 471–475 (2013).
Novak, I. Mitophagy: a complex mechanism of mitochondrial removal. Antioxid. Redox Signal. 17, 794–802 (2012).
Karbowski, M. & Youle, R.J. Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation. Curr. Opin. Cell Biol. 23, 476–482 (2011).
Kane, L.A. et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 205, 143–153 (2014).
Koyano, F. et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510, 162–166 (2014).
Kazlauskaite, A. et al. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem. J. 460, 127–139 (2014).
Bingol, B. et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature 510, 370–375 (2014).
Müller-Rischart, A.K. et al. The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO. Mol. Cell 49, 908–921 (2013).
Tai, H.C. et al. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am. J. Pathol. 181, 1426–1435 (2012).
Wong, H.K. et al. Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism. Hum. Mol. Genet. 17, 3223–3235 (2008).
Wang, Y. et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153–4170 (2009).
Wooten, M.W. et al. Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins. J. Biol. Chem. 283, 6783–6789 (2008).
Babu, J.R., Geetha, T. & Wooten, M.W. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J. Neurochem. 94, 192–203 (2005).
Wang, Y. et al. Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation. Autophagy 6, 182–183 (2010).
Keck, S., Nitsch, R., Grune, T. & Ullrich, O. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease. J. Neurochem. 85, 115–122 (2003).
Schaeffer, V. & Goedert, M. Stimulation of autophagy is neuroprotective in a mouse model of human tauopathy. Autophagy 8, 1686–1687 (2012).
Zucchelli, S. et al. Tumor necrosis factor receptor-associated factor 6 (TRAF6) associates with huntingtin protein and promotes its atypical ubiquitination to enhance aggregate formation. J. Biol. Chem. 286, 25108–25117 (2011).
Bennett, E.J. et al. Global changes to the ubiquitin system in Huntington's disease. Nature 448, 704–708 (2007).
Wang, J. et al. Impaired ubiquitin-proteasome system activity in the synapses of Huntington's disease mice. J. Cell Biol. 180, 1177–1189 (2008).
Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004).
Cohen, S. et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J. Cell Biol. 185, 1083–1095 (2009).
Glass, D.J. Molecular mechanisms modulating muscle mass. Trends Mol. Med. 9, 344–350 (2003).
Sacheck, J.M., Ohtsuka, A., McLary, S.C. & Goldberg, A.L. IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am. J. Physiol. Endocrinol. Metab. 287, E591–E601 (2004).
Sandri, M. et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117, 399–412 (2004).
Stitt, T.N. et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol. Cell 14, 395–403 (2004).
Rommel, C. et al. Mediation of IGF-1–induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat. Cell Biol. 3, 1009–1013 (2001).
Lagirand-Cantaloube, J. et al. Inhibition of atrogin-1/MAFbx mediated MyoD proteolysis prevents skeletal muscle atrophy in vivo. PLoS ONE 4, e4973 (2009).
Cohen, S., Zhai, B., Gygi, S.P. & Goldberg, A.L. Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy. J. Cell Biol. 198, 575–589 (2012).
Quy, P.N., Kuma, A., Pierre, P. & Mizushima, N. Proteasome-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) is essential for autophagy suppression and muscle remodeling following denervation. J. Biol. Chem. 288, 1125–1134 (2013).
Altun, M. et al. Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway. J. Biol. Chem. 285, 39597–39608 (2010).
Arndt, V., Daniel, C., Nastainczyk, W., Alberti, S. & Hohfeld, J. BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP. Mol. Biol. Cell 16, 5891–5900 (2005).
Arndt, V. et al. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr. Biol. 20, 143–148 (2010).
Biddinger, S.B. & Kahn, C.R. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123–158 (2006).
Posner, B.I. Regulation of insulin receptor kinase activity by endosomal processes: possible areas for therapeutic intervention. Curr. Opin. Investig. Drugs 4, 430–434 (2003).
White, M.F. IRS proteins and the common path to diabetes. Am. J. Physiol. Endocrinol. Metab. 283, E413–E422 (2002).
Rui, L., Yuan, M., Frantz, D., Shoelson, S. & White, M.F. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 277, 42394–42398 (2002).
Donath, M.Y. & Shoelson, S.E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).
Kim, S.J. et al. mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8. Mol. Cell 48, 875–887 (2012).
Song, R. et al. Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. Nature 494, 375–379 (2013).
Hussein, M.A. Nontraditional cytotoxic therapies for relapsed/refractory multiple myeloma. Oncologist 7 (suppl. 1), 20–29 (2002).
Cheson, B.D. Hematologic malignancies: new developments and future treatments. Semin. Oncol. 29, 33–45 (2002).
Lawasut, P. et al. New proteasome inhibitors in myeloma. Curr. Hematol. Malig. Rep. 7, 258–266 (2012).
Fostier, K., De Becker, A. & Schots, R. Carfilzomib: a novel treatment in relapsed and refractory multiple myeloma. Onco. Targets Ther. 5, 237–244 (2012).
Catley, L. et al. Aggresome induction by proteasome inhibitor bortezomib and α-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 108, 3441–3449 (2006).
Hideshima, T. et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 107, 4053–4062 (2006).
Mitsiades, C.S. et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc. Natl. Acad. Sci. USA 101, 540–545 (2004).
Kuhn, D.J. et al. Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood 113, 4667–4676 (2009).
Lee, W. & Kim, K.B. The immunoproteasome: an emerging therapeutic target. Curr. Top. Med. Chem. 11, 2923–2930 (2011).
Basler, M., Dajee, M., Moll, C., Groettrup, M. & Kirk, C.J. Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J. Immunol. 185, 634–641 (2010).
Muchamuel, T. et al. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat. Med. 15, 781–787 (2009).
Yang, Y. Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res. 67, 9472–9481 (2007).
Xu, G.W. et al. The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma. Blood 115, 2251–2259 (2010).
Soucy, T.A. et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458, 732–736 (2009).
Wenzel, D.M., Stoll, K.E. & Klevit, R.E. E2s: structurally economical and functionally replete. Biochem. J. 433, 31–42 (2011).
Bedford, L., Lowe, J., Dick, L.R., Mayer, R.J. & Brownell, J.E. Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat. Rev. Drug Disc. 10, 29–46 (2011).
Rape, M. Assembly of k11-linked ubiquitin chains by the anaphase-promoting complex. Subcell. Biochem. 54, 107–115 (2010).
Dou, H., Buetow, L., Sibbet, G.J., Cameron, K. & Huang, D.T. BIRC7–E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nat. Struct. Mol. Biol. 19, 876–883 (2012).
Pruneda, J.N. et al. Structure of an E3:E2∼Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol. Cell 47, 933–942 (2012).
Deshaies, R.J. & Joazeiro, C.A. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399–434 (2009).
Yang, Y. et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7, 547–559 (2005).
Li, Q. & Lozano, G. Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin. Cancer Res. 19, 34–41 (2013).
Sosin, A.M. et al. HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J. Hematol. Oncol. 5, 57 (2012).
Fulda, S. & Vucic, D. Targeting IAP proteins for therapeutic intervention in cancer. Nat. Rev. Drug Discov. 11, 109–124 (2012).
Vince, J.E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007).
Varfolomeev, E. et al. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor-α (TNFα)-induced NF-κB activation. J. Biol. Chem. 283, 24295–24299 (2008).
Bertrand, M.J. et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 30, 689–700 (2008).
Lill, J.R. & Wertz, I.E. Toward understanding ubiquitin-modifying enzymes: from pharmacological targeting to proteomics. Trends Pharmacol. Sci. 35, 187–207 (2014).
Wang, Z. et al. Skp2 is a promising therapeutic target in breast cancer. Front. Oncol. 1, 57 (2012).
Bernassola, F., Karin, M., Ciechanover, A. & Melino, G. The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell 14, 10–21 (2008).
Trempe, J.F. et al. Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science 340, 1451–1455 (2013).
Duda, D.M. et al. Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoinhibition of an Ariadne-family E3 and insights into ligation mechanism. Structure 21, 1031–1041 (2013).
Frye, J.J. et al. Electron microscopy structure of human APC/C-EMI1 reveals multimodal mechanism of E3 ligase shutdown. Nat. Struct. Mol. Biol. 20, 827–835 (2013).
Fraile, J.M., Quesada, V., Rodriguez, D., Freije, J.M. & Lopez-Otin, C. Deubiquitinases in cancer: new functions and therapeutic options. Oncogene 31, 2373–2388 (2012).
Chauhan, D. et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 22, 345–358 (2012).
Reverdy, C. et al. Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme. Chem. Biol. 19, 467–477 (2012).
Liang, Q. et al. A selective USP1–UAF1 inhibitor links deubiquitination to DNA damage responses. Nat. Chem. Biol. 10, 298–304 (2014).
Lee, B.H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179–184 (2010).
D'Arcy, P. et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat. Med. 17, 1636–1640 (2011).
Walczak, H., Iwai, K. & Dikic, I. Generation and physiological roles of linear ubiquitin chains. BMC Biol. 10, 23 (2012).
López-Mosqueda, J. & Dikic, I. Deciphering functions of branched ubiquitin chains. Cell 157, 767–769 (2014).
Meyer, H.J. & Rape, M. Enhanced protein degradation by branched ubiquitin chains. Cell 157, 910–921 (2014).
Rubinsztein, D.C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709–730 (2012).
Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N. & Rubinsztein, D.C. α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003).
Spencer, B. et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in α-synuclein models of Parkinson's and Lewy body diseases. J. Neurosci. 29, 13578–13588 (2009).
Williams, A. et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol. 4, 295–305 (2008).
Yang, Y. et al. Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Disc. 4, 480–493 (2014).
Ernst, A. et al. A strategy for modulation of enzymes in the ubiquitin system. Science 339, 590–595 (2013).
Acknowledgements
We apologize to all scientists whose important contribution was not referenced in this Review due to space limitations. We would like to thank members of the Vucic and Dikic laboratories for critical comments on the manuscript. This work was supported by grants from Deutsche Forschungsgemeinschaft (DI 931/3-1; BE 4685/1-1), the Cluster of Excellence “Macromolecular Complexes” of the Goethe University Frankfurt (EXC115), LOEWE grant Ub-Net and LOEWE Centrum for Gene and Cell therapy Frankfurt and the European Research Council / ERC grant agreement n° 250241-LineUb to ID. Domagoj Vucic is an employee of Genentech.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Popovic, D., Vucic, D. & Dikic, I. Ubiquitination in disease pathogenesis and treatment. Nat Med 20, 1242–1253 (2014). https://doi.org/10.1038/nm.3739
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.3739
This article is cited by
-
USP54 is a potential therapeutic target in castration-resistant prostate cancer
BMC Urology (2024)
-
TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors
British Journal of Cancer (2024)
-
The E3 ubiquitin ligase TRIM39 modulates renal fibrosis induced by unilateral ureteral obstruction through regulating proteasomal degradation of PRDX3
Cell Death Discovery (2024)
-
E3 ligase TRIM65 alleviates intestinal ischemia/reperfusion injury through inhibition of TOX4-mediated apoptosis
Cell Death & Disease (2024)
-
HRD1-induced TMEM2 ubiquitination promotes ER stress-mediated apoptosis through a non-canonical pathway in intestinal ischemia/reperfusion
Cell Death & Disease (2024)
