Abstract
The transcription factor nuclear factor-kappa B (NF-κB) controls a number of essential cellular functions, including the immune response, cell proliferation, and apoptosis. NF-κB signaling must be engaged temporally and spatially and well orchestrated to prevent aberrant activation because loss of normal regulation of NF-κB is a major contributor to a variety of pathological diseases, including inflammatory diseases, autoimmune diseases, and cancers. Thus, understanding the molecular mechanisms controlling NF-κB activation is an important part of treatment of these relevant diseases. Although NF-κB transcriptional activity is largely regulated by nuclear translocation, post-translational modification of NF-κB signaling components, including phosphorylation, ubiquitination, acetylation, and methylation, has emerged as an important mechanism affecting activity. Many proteins have been shown to ubiquitinate and regulate NF-κB activation at the receptor signaling complex in response to a variety of ligands, such as tumor necrosis factor, interleukin-1, and Toll-like receptor ligands. In this review, we discuss our current knowledge of ubiquitination patterns and their functional role in NF-κB regulation.
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Alameda JP, Fernández-Aceñero MJ, Quintana RM, Page A, Ramírez Á, Navarro M, Casanova ML (2013) Functional inactivation of CYLD promotes the metastatic potential of tumor epidermal cells. J Invest Dermatol 133:1870–1878
Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, Ben-Neriah Y (1995) Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappaB inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 92:10599–10603
Ben-Neriah Y (2002) Regulatory functions of ubiquitination in the immune system. Nat Immunol 3:20–26
Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, Barker PA (2008) cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell 30:689–700
Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR, Jones C, Hansen J, Blair E, Hofmann B, Siebert R, Turner G, Evans DG, Schrander-Stumpel C, Beemer FA, van Den Ouweland A, Halley D, Delpech B, Cleveland MG, Leigh I, Leisti J, Rasmussen S (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25:160–165
Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O, McNally E, Pickart C, Ma A (2004) The ubiquitin-modifyingenzymeA20 is required for termination of toll-like receptor responses. Nat Immunol 5:1052–1060
Brummelkamp TR, Nijman SM, Dirac AM, Bernards R (2003) Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424:797–801
Byun HS, Park KA, Won M, Yang KJ, Shin S, Piao L, Kwak JY, Lee ZW, Park J, Seok JH, Liu ZG, Hur GM (2006) Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling complex: implication for the regulatory role of protein kinase C. Mol Pharmacol 70:1099–1108
Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7:758–765
Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296:1634–1635
Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T (1995) Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev 9:1586–1597
Chen ZJ, Parent L, Maniatis T (1996) Site-specific phosphorylation of IkappaB alpha by a novel ubiquitination-dependent protein kinase activity. Cell 84:853–862
Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (2000) Activation of the IkappaB kinase complex by TRAF6requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103(2):351–361
Dixit VM, Green S, Sarma V, Holzman LB, Wolf FW, O’Rourke K, Ward PA, Prochownik EV, Marks RM (1990) Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. J Biol Chem 265(5):2973–2978
Doherty FJ, Dawson S, Mayer RJ (2002) The ubiquitin-proteasome pathway of intracellular proteolysis. Essays Biochem 38:51–63
Elliott PR, Nielsen SV, Marco-Casanova P, Fiil BK, Keusekotten K, Mailand N, Freund SM, Gyrd-Hansen M, Komander D (2014) Molecular basis and regulation of OTULIN–LUBAC interaction. Mol Cell 54(3):335–348
Fujita H, Rahighi S, Akita M, Kato R, Sasaki Y, Wakatsuki S, Iwai K (2014) Mechanism underlying IκB kinase activation mediated by the linear ubiquitin chain assembly complex. Mol Cell Biol 34(7):1322–1335
Gerondakis S, Morrice N, Richardson IB, Wettenhall R, Fecondo J, Grumont RJ (1993) The activity of a 70 kDa IκB molecule identical to the carboxyl terminus of the p105 NF-κB precursor is modulated by protein kinase A. Cell Growth Differ 4:617–627
Ghosh S, May MJ, Kopp EB (1998) NF-κB and Rel proteins: evolutionary conserved mediators of immune responses. Annu Rev Immunol 16:225–260
Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T, Koschny R, Komander D, Silke J, Walczak H (2009) Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 36(5):831–844
Häcker H, Karin M (2006) Regulation and function of IKK and IKK-related kinases. Sci STKE 356(re13):1–19
Hayashi M, Jono H, Shinriki S, Nakamura T, Guo J, Sueta A, Tomiguchi M, Fujiwara S, Yamamoto-Ibusuki M, Murakami K, Yamashita S, Yamamoto Y, Li JD, Iwase H, Ando Y (2014) Clinical significance of CYLD downregulation in breast cancer. Breast Cancer Res Treat 143:447–457
Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132(3):344–362
Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479
Humphries F, Moynagh PN (2015) Molecular and physiological roles of Pellino E3 ubiquitin ligases in immunity. Immunol Rev 266(1):93–108
Hur GM, Lewis J, Yang Q, Lin Y, Nakano H, Nedospasov S, Liu ZG (2003) The death domain kinase RIP has an essential role in DNA damage-induced NF-kappa B activation. Genes Dev 17(7):873–882
Inoue J, Kerr LD, Kakizuka A, Verma IM (1992) I kappa B gamma, a 70 kDa protein identical to the C-terminal half of p100 NF-κB: a new member of the IκB family. Cell 68(6):1109–1120
Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K (2003) Role of the TAB 2-related protein TAB 3 in IL-1 and TNF signaling. EMBO J 22(23):6277–6288
Jeon J, Lee JH, Park KA, Byun HS, Lee H, Lee Y, Zhang T, Kang K, Seok JH, Kwon HJ, Han MD, Kang SW, Hong JH, Hur GM (2014) Brazilin selectively disrupts proximal IL-1 receptor signaling complex formation by targeting an IKK-upstream signaling components. Biochem Pharmacol 89(4):515–525
Jin W, Chang M, Paul EM, Babu G, Lee AJ, Reiley W, Wright A, Zhang M, You J, Sun SC (2008) Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest 118:1858–1866
Kanarek N, Ben-Neriah Y (2012) Regulation of NF-κB by ubiquitination and degradation of the IκBs. Immunol Rev 246(1):77–94
Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 18:621–663
Kinoshita H, Okabe H, Beppu T, Chikamoto A, Hayashi H, Imai K, Mima K, Nakagawa S, Yokoyama N, Ishiko T, Shinriki S, Jono H, Ando Y, Baba H (2013) CYLD downregulation is correlated with tumor development in patients with hepatocellular carcinoma. Mol Clin Oncol 1:309–314
Kornitzer D, Ciechanover A (2000) Modes of regulation of ubiquitin-mediated protein degradation. Cell Physiol 182(1):1–11
Kovalenko A, Chable-Bessia C, Cantarella G, Israël A, Wallach D, Courtois G (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424:801–805
Krappmann D, Scheidereit C (2005) A pervasive role of ubiquitin conjugation in activation and termination of IkappaB kinase pathways. EMBO Rep 6(4):321–326
Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A (2000) Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289(5488):2350–2354
Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2:725–734
Marienfeld R, May MJ, Berberich I, Serfling E, Ghosh G, Neumann M (2003) RelB forms transcriptionally inactive complexes with RelA/p65. J Biol Chem 278:19852–19860
Massoumi R (2011) CYLD: a deubiquitination enzyme with multiple roles in cancer. Future Oncol 7:285–297
Nagy N, Farkas K, Kemény L, Széll M (2015) Phenotype-genotype correlations for clinical variants caused by CYLD mutations. Eur J Med Genet 58:271–278
Nomoto J, Hiramoto N, Kato M, Sanada M, Maeshima AM, Taniguchi H, Hosoda F, Asakura Y, Munakata W, Sekiguchi N, Maruyama D, Watanabe T, Nakagama H, Takeuchi K, Tobinai K, Ogawa S, Kobayashi Y (2012) Deletion of the TNFAIP3/A20 gene detected by FICTION analysis in classical Hodgkin lymphoma. BMC Cancer 12:457
Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin-proteasome pathway is required for processing the NF-kappaB1precursorprotein and the activation of NF-kappaB. Cell 78(5):773–785
Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G, Roelofs J, Finley D, Gygi SP (2003) A proteomics approach to understanding protein ubiquitination. Nat Biotechnol 21(8):921–926
Pickart CM (2004) Back to the future with ubiquitin. Cell 116(2):181–190
Pomerantz JL, Baltimore D (2002) Two pathways to NF-κB. Mol Cell 10:693–701
Reiley W, Zhang M, Wu X, Granger E, Sun SC (2005) Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Mol Cell Biol 25:3886–3895
Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M, Sun SC (2007) Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 204:1475–1485
Renner F, Schmitz ML (2009) Autoregulatory feedback loops terminating the NF-kappaB response. Trends Biochem Sci 34:128–135
Rieser E, Cordier SM, Walczak H (2013) Linear ubiquitination: a newly discovered regulator of cell signalling. Trends Biochem Sci 38(2):94–102
Roos-Mattjus P, Sistonen L (2004) The ubiquitin-proteasome pathway. Ann Med 36(4):285–295
Schaeffer V, Akutsu M, Olma MH, Gomes LC, Kawasaki M, Dikic I (2014) Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling. Mol Cell 54(3):349–361
Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G, Klapper W, Vater I, Giefing M, Gesk S, Stanelle J, Siebert R, Küppers R (2009) TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 206(5):981–989
Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun S-C, Karin M (2001) Activation by IKKα of a second evolutionary conserved, NF-κB signaling pathway. Science 293(5534):1495–1499
Shembade N, Harhaj EW (2012) Regulation of NF-κB signaling by the A20 deubiquitinase. Cell Mol Immunol 9:123–130
Shi CS, Kehrl JH (2003) Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2). J Biol Chem 278(17):15429–15434
Shimizu Y, Taraborrelli L, Walczak H (2015) Linear ubiquitination in immunity. Immunol Rev 266(1):190–207
Skaug B, Jiang X, Chen ZJ (2009) The role of ubiquitin in NF-kappaB regulatory pathways. Annu Rev Biochem 78:769–796
Smit JJ, van Dijk WJ, El Atmioui D, Merkx R, Ovaa H, Sixma TK (2013) Target specificity of the E3 ligase LUBAC for ubiquitin and NEMO relies on different minimal requirements. J BiolChem 288(44):31728–31737
Spratt DE, Walden H, Shaw GS (2014) RBR E3 ubiquitin ligases: new structures, new insights, new questions. Biochem J 458(3):421–437
Stieglitz B, Rana RR, Koliopoulos MG, Morris-Davies AC, Schaeffer V, Christodoulou E, Howell S, Brown NR, Dikic I, Rittinger K (2013) Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature 503(7476):422–426
Sun SC (2008) Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8:501–511
Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J, Matsumoto K, Gaynor RB (2003) TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. J Mol Biol 326(1):105–115
Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K (2009) Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11:123–132
Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424:793–796
Vallabhapurapu S, Karin M (2009) Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27:693–733
Varfolomeev E, Goncharov T, Fedorova AV, Dynek JN, Zobel K, Deshayes K, Fairbrother WJ, Vucic D (2008) c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J Biol Chem 283(36):24295–24299
Verstak B, Nagpal K, Bottomley SP, Golenbock DT, Hertzog PJ, Mansell A (2009) MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses. J Biol Chem 284:24192–24203
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412(6844):346–351
Wang S, Wen F, Wiley GB, Kinter MT, Gaffney PM (2013) An enhancer element harboring variants associated with systemic lupus erythematosus engages the TNFAIP3 promoter to influence A20 expression. PLoS Genet 9(9):e1003750
Wertz I, Dixit V (2014) A20-a bipartite ubiquitin editing enzyme with immunoregulatory potential. Adv Exp Med Biol 809:1–12
Wertz IE, O’Rourke KM, Wu P, Wiesmann C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430:694–699
Windheim M, Stafford M, Peggie M, Cohen P (2008) Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase. Mol Cell Biol 28:1783–1791
Won M, Park KA, Byun HS, Sohn KC, Kim YR, Jeon J, Hong JH, Park J, Seok JH, Kim JM, Yoon WH, Jang IS, Shen HM, Liu ZG, Hur GM (2010) Novel anti-apoptotic mechanism of A20 through targeting ASK1 to suppress TNF-induced JNK activation. Cell Death Differ 17(12):1830–1841
Wright A, Reiley WW, Chang M, Jin W, Lee AJ, Zhang M, Sun SC (2007) Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. Dev Cell 13:705–716
Xiao G, Harhaj EW, Sun SC (2001) NF-kappaB-inducing kinase regulates the processing of NF-κB2 p100. Mol Cell 7:401–409
Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F, Ben-Neriah Y (1998) Identification of the receptor component of the I kappaB alpha-ubiquitin ligase. Nature 396(6711):590–594
Yoon HK, Byun HS, Lee H, Jeon J, Lee Y, Li Y, Jin EH, Kim J, Hong JH, Kim JH, Seok JH, Kang SW, Lee WH, Hur GM (2013) Intron-derived aberrant splicing of A20 transcript in rheumatoid arthritis. Rheumatology (Oxford) 52(3):427–437
Zhang J, Stirling B, Temmerman ST, Ma CA, Fuss IJ, Derry JM, Jain A (2006) Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. J Clin Invest 116:3042–3049
Zhang T, Park KA, Li Y, Byun HS, Jeon J, Lee Y, Hong JH, Kim JM, Huang SM, Choi SW, Kim SH, Sohn KC, Ro H, Lee JH, Lu T, Stark GR, Shen HM, Liu ZG, Park J, Hur GM (2013) PHF20 regulates NF-κB signalling by disrupting recruitment of PP2A to p65. Nat Commun 4:2062
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This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (No. 2014R1A2A1A01004363), by Ministry of Education (NRF-2014R1A6A1029617), and by research fund of Chungnam National University.
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Won, M., Byun, H.S., Park, K.A. et al. Post-translational control of NF-κB signaling by ubiquitination. Arch. Pharm. Res. 39, 1075–1084 (2016). https://doi.org/10.1007/s12272-016-0772-2
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DOI: https://doi.org/10.1007/s12272-016-0772-2