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Immune Homeostasis: Activation and Downregulation of NF-κB

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Ubiquitin Chains: Degradation and Beyond

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Abstract

This chapter broadly introduces the innate and adaptive immune system, focusing on the critical role of the nuclear factor κB (NF-κB) family of transcription factors. While NF-κB was originally discovered 25 years ago as a regulator of κ light chain in B cells, research in the topic has diversified enormously and NF-κB has since been the focus of extensive research in multiple areas of biomedical science. Today, a search in PubMed using “NF-κB” alone results in more than 60,000 hits. The transcription factor controls the expression of multiple genes that are involved in regulating inflammation and shaping the immune response. Therefore in order to avoid autoimmunity, it is essential that the activation of NF-κB be tightly regulated so as to limit both the duration and magnitude of the immune response. This chapter explores broader themes that have emerged for NF-κB activation, and the possible role of regulatory ubiquitination in NF-κB activation.

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References

  1. Dethlefsen L, McFall-Ngai M, Relman DA (2007) An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 449:811–818

    CAS  PubMed  Google Scholar 

  2. Smith DA, Germolec DR (1999) Introduction to immunology and autoimmunity. Environ Health Perspect 107(Suppl 5):661–665

    PubMed Central  PubMed  Google Scholar 

  3. Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1:135–145

    CAS  PubMed  Google Scholar 

  4. Gregersen PK, Behrens TW (2006) Genetics of autoimmune diseases—disorders of immune homeostasis. Nat Rev Genet 7:917–928

    CAS  PubMed  Google Scholar 

  5. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995

    CAS  PubMed  Google Scholar 

  6. Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54(Pt 1):1–13

    CAS  PubMed  Google Scholar 

  7. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216

    CAS  PubMed  Google Scholar 

  8. Linehan SA, Martinez-Pomares L, Gordon S (2000) Macrophage lectins in host defence. Microbes Infect 2:279–288

    CAS  PubMed  Google Scholar 

  9. Chen G, Shaw MH, Kim YG, Nunez G (2009) NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol 4:365–398

    CAS  PubMed  Google Scholar 

  10. Franchi L, Warner N, Viani K, Nunez G (2009) Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev 227:106–128

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Inohara N, Nunez G (2003) NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3:371–382

    CAS  PubMed  Google Scholar 

  12. Yoneyama M, Fujita T (2009) RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 227:54–65

    CAS  PubMed  Google Scholar 

  13. Johannessen M, Askarian F, Sangvik M, Sollid JE (2013) Bacterial interference with canonical NFkappaB signaling. Microbiology 159(Pt 10):2001–2013. doi:10.1099/mic.0.069369-0

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22(2):240–273, Table of Contents

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Courtois G, Gilmore TD (2006) Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene 25:6831–6843

    CAS  PubMed  Google Scholar 

  16. Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–759

    CAS  PubMed  Google Scholar 

  17. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436

    CAS  PubMed  Google Scholar 

  18. Ma A, Malynn BA (2012) A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 12:774–785

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Hayden MS, West AP, Ghosh S (2006) NF-kappaB and the immune response. Oncogene 25:6758–6780

    CAS  PubMed  Google Scholar 

  20. Sen R, Baltimore D (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46:705–716

    CAS  PubMed  Google Scholar 

  21. Sen R, Baltimore D (1986) Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 47:921–928

    CAS  PubMed  Google Scholar 

  22. Baeuerle PA, Baltimore D (1988) Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell 53:211–217

    CAS  PubMed  Google Scholar 

  23. Hinz M, Arslan SÇ, Scheidereit C (2012) It takes two to tango: IκBs, the multifunctional partners of NF-κB. Immunol Rev 246:59–76

    PubMed  Google Scholar 

  24. Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132:344–362

    CAS  PubMed  Google Scholar 

  25. Hoffmann A, Natoli G, Ghosh G (2006) Transcriptional regulation via the NF-kappaB signaling module. Oncogene 25:6706–6716

    CAS  PubMed  Google Scholar 

  26. Perkins ND (2006) Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene 25:6717–6730

    CAS  PubMed  Google Scholar 

  27. Wan F et al (2007) Ribosomal protein S3: a KH domain subunit in NF-kappaB complexes that mediates selective gene regulation. Cell 131:927–939

    CAS  PubMed  Google Scholar 

  28. Liou HC, Nolan GP, Ghosh S, Fujita T, Baltimore D (1992) The NF-kappa B p50 precursor, p105, contains an internal I kappa B-like inhibitor that preferentially inhibits p50. EMBO J 11:3003–3009

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Dobrzanski P, Ryseck RP, Bravo R (1995) Specific inhibition of RelB/p52 transcriptional activity by the C-terminal domain of p100. Oncogene 10:1003–1007

    CAS  PubMed  Google Scholar 

  30. Whiteside ST, Israel A (1997) I kappa B proteins: structure, function and regulation. Semin Cancer Biol 8:75–82

    CAS  PubMed  Google Scholar 

  31. Weil R, Whiteside ST, Israel A (1997) Control of NF-kappa B activity by the I kappa B beta inhibitor. Immunobiology 198:14–23

    CAS  PubMed  Google Scholar 

  32. Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621–663

    CAS  PubMed  Google Scholar 

  33. Thompson JE, Phillips RJ, Erdjument-Bromage H, Tempst P, Ghosh S (1995) I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell 80:573–582

    CAS  PubMed  Google Scholar 

  34. Suyang H, Phillips R, Douglas I, Ghosh S (1996) Role of unphosphorylated, newly synthesized I kappa B beta in persistent activation of NF-kappa B. Mol Cell Biol 16:5444–5449

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Li Z, Nabel GJ (1997) A new member of the I kappaB protein family, I kappaB epsilon, inhibits RelA (p65)-mediated NF-kappaB transcription. Mol Cell Biol 17:6184–6190

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Whiteside ST, Epinat JC, Rice NR, Israel A (1997) I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel NF-kappa B activity. EMBO J 16:1413–1426

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Ghosh S, Baltimore D (1990) Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature 344:678–682

    CAS  PubMed  Google Scholar 

  38. Naumann M, Scheidereit C (1994) Activation of NF-kappa B in vivo is regulated by multiple phosphorylations. EMBO J 13:4597–4607

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485–1488

    CAS  PubMed  Google Scholar 

  40. Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY, Ballard DW (1995) Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol 15:2809–2818

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Alkalay I, Yaron A, Hatzubai A, Jung S, Avraham A, Gerlitz O, Pashut-Lavon I, Ben-Neriah Y (1995) In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B. Mol Cell Biol 15:1294–1301

    PubMed Central  CAS  PubMed  Google Scholar 

  42. DiDonato JA, Mercurio F, Karin M (1995) Phosphorylation of I kappa B alpha precedes but is not sufficient for its dissociation from NF-kappa B. Mol Cell Biol 15:1302–1311

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Finco TS, Beg AA, Baldwin AS Jr (1994) Inducible phosphorylation of I kappa B alpha is not sufficient for its dissociation from NF-kappa B and is inhibited by protease inhibitors. Proc Natl Acad Sci U S A 91:11884–11888

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Lin R, Beauparlant P, Makris C, Meloche S, Hiscott J (1996) Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability. Mol Cell Biol 16:1401–1409

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Miyamoto S, Maki M, Schmitt MJ, Hatanaka M, Verma IM (1994) Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B. Proc Natl Acad Sci U S A 91:12740–12744

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Beg AA, Finco TS, Nantermet PV, Baldwin AS Jr (1993) Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol Cell Biol 13:3301–3310

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Brown K, Park S, Kanno T, Franzoso G, Siebenlist U (1993) Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. Proc Natl Acad Sci U S A 90:2532–2536

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Mellits KH, Hay RT, Goodbourn S (1993) Proteolytic degradation of MAD3 (I kappa B alpha) and enhanced processing of the NF-kappa B precursor p105 are obligatory steps in the activation of NF-kappa B. Nucleic Acids Res 21:5059–5066

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Sun SC, Ganchi PA, Ballard DW, Greene WC (1993) NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science 259:1912–1915

    CAS  PubMed  Google Scholar 

  50. Lin YC, Brown K, Siebenlist U (1995) Activation of NF-kappa B requires proteolysis of the inhibitor I kappa B-alpha: signal-induced phosphorylation of I kappa B-alpha alone does not release active NF-kappa B. Proc Natl Acad Sci U S A 92:552–556

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Henkel T, Machleidt T, Alkalay I, Kronke M, Ben-Neriah Y, Baeuerle PA (1993) Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature 365:182–185

    CAS  PubMed  Google Scholar 

  52. 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

    CAS  PubMed  Google Scholar 

  53. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78:773–785

    CAS  PubMed  Google Scholar 

  54. Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, Ben-Neriah Y (1995) Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 92:10599–10603

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Spencer E, Jiang J, Chen ZJ (1999) Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP. Genes Dev 13:284–294

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Tan P, Fuchs SY, Chen A, Wu K, Gomez C, Ronai Z, Pan ZQ (1999) Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha. Mol Cell 3:527–533

    CAS  PubMed  Google Scholar 

  57. Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW (1999) The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev 13:270–283

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Yaron A et al (1998) Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature 396:590–594

    CAS  PubMed  Google Scholar 

  59. Hoffmann A, Levchenko A, Scott ML, Baltimore D (2002) The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science 298:1241–1245

    CAS  PubMed  Google Scholar 

  60. Chen L, Fischle W, Verdin E, Greene WC (2001) Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293:1653–1657

    CAS  Google Scholar 

  61. Arenzana-Seisdedos F, Turpin P, Rodriguez M, Thomas D, Hay RT, Virelizier JL, Dargemont C (1997) Nuclear localization of I kappa B alpha promotes active transport of NF-kappa B from the nucleus to the cytoplasm. J Cell Sci 110(Pt 3):369–378

    CAS  PubMed  Google Scholar 

  62. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (1997) The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91:243–252

    CAS  PubMed  Google Scholar 

  63. Mercurio F et al (1997) IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science 278:860–866

    CAS  PubMed  Google Scholar 

  64. Rothwarf DM, Zandi E, Natoli G, Karin M (1998) IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 395:297–300

    CAS  PubMed  Google Scholar 

  65. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV (1997) IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science 278:866–869

    CAS  PubMed  Google Scholar 

  66. Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, Israel A (1998) Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93:1231–1240

    CAS  PubMed  Google Scholar 

  67. Lawrence T, Bebien M, Liu GY, Nizet V, Karin M (2005) IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 434:1138–1143

    CAS  PubMed  Google Scholar 

  68. Shih VF, Tsui R, Caldwell A, Hoffmann A (2011) A single NFkappaB system for both canonical and non-canonical signaling. Cell Res 21:86–102

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Rudolph D, Yeh W-C, Wakeham A, Rudolph B, Nallainathan D, Potter J, Elia AJ, Mak TW (2000) Severe liver degeneration and lack of NF-κB activation in NEMO/IKKγ-deficient mice. Genes Dev 14:854–862

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Delhase M, Hayakawa M, Chen Y, Karin M (1999) Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 284:309–313

    CAS  PubMed  Google Scholar 

  71. Li Q, Antwerp DV, Mercurio F, Lee K-F, Verma IM (1999) Severe Liver Degeneration in Mice Lacking the IκB Kinase 2 Gene. Science 284:321–325

    CAS  PubMed  Google Scholar 

  72. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D (1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376:167–170

    CAS  PubMed  Google Scholar 

  73. Huang TT, Kudo N, Yoshida M, Miyamoto S (2000) A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes. Proc Natl Acad Sci U S A 97:1014–1019

    PubMed Central  CAS  PubMed  Google Scholar 

  74. Johnson C, Van Antwerp D, Hope TJ (1999) An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IkappaBalpha. EMBO J 18:6682–6693

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Chen ZJ, Parent L, Maniatis T (1996) Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 84:853–862

    CAS  PubMed  Google Scholar 

  76. Scheidereit C (2006) IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene 25:6685–6705

    CAS  PubMed  Google Scholar 

  77. Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96

    CAS  PubMed  Google Scholar 

  78. Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288

    CAS  PubMed  Google Scholar 

  79. Novack DV, Yin L, Hagen-Stapleton A, Schreiber RD, Goeddel DV, Ross FP, Teitelbaum SL (2003) The IkappaB function of NF-kappaB2 p100 controls stimulated osteoclastogenesis. J Exp Med 198:771–781

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Saitoh T, Nakayama M, Nakano H, Yagita H, Yamamoto N, Yamaoka S (2003) TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation. J Biol Chem 278:36005–36012

    CAS  PubMed  Google Scholar 

  81. Claudio E, Brown K, Park S, Wang H, Siebenlist U (2002) BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol 3:958–965

    CAS  PubMed  Google Scholar 

  82. Coope HJ, Atkinson PG, Huhse B, Belich M, Janzen J, Holman MJ, Klaus GG, Johnston LH, Ley SC (2002) CD40 regulates the processing of NF-kappaB2 p100 to p52. EMBO J 21:5375–5385

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Fusco AJ, Savinova OV, Talwar R, Kearns JD, Hoffmann A, Ghosh G (2008) Stabilization of RelB requires multidomain interactions with p100/p52. J Biol Chem 283:12324–12332

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Basak S, Shih VF, Hoffmann A (2008) Generation and activation of multiple dimeric transcription factors within the NF-kappaB signaling system. Mol Cell Biol 28:3139–3150

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Yilmaz ZB, Weih DS, Sivakumar V, Weih F (2003) RelB is required for Peyer’s patch development: differential regulation of p52-RelB by lymphotoxin and TNF. EMBO J 22:121–130

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Senftleben U et al (2001) Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293:1495–1499

    CAS  PubMed  Google Scholar 

  87. Xiao G, Harhaj EW, Sun SC (2001) NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 7:401–409

    CAS  PubMed  Google Scholar 

  88. Liang C, Zhang M, Sun SC (2006) beta-TrCP binding and processing of NF-kappaB2/p100 involve its phosphorylation at serines 866 and 870. Cell Signal 18:1309–1317

    CAS  PubMed  Google Scholar 

  89. Amir RE, Haecker H, Karin M, Ciechanover A (2004) Mechanism of processing of the NF-kappa B2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase. Oncogene 23:2540–2547

    CAS  PubMed  Google Scholar 

  90. Xiao G, Fong A, Sun SC (2004) Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation. J Biol Chem 279:30099–30105

    CAS  PubMed  Google Scholar 

  91. Yin L, Wu L, Wesche H, Arthur CD, White JM, Goeddel DV, Schreiber RD (2001) Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIK-deficient mice. Science 291:2162–2165

    CAS  PubMed  Google Scholar 

  92. Fagarasan S, Shinkura R, Kamata T, Nogaki F, Ikuta K, Tashiro K, Honjo T (2000) Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system. J Exp Med 191:1477–1486

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, Suzuki M, Kogishi K, Serikawa T, Honjo T (1999) Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat Genet 22:74–77

    CAS  PubMed  Google Scholar 

  94. Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, Johnson R, Karin M (1999) The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 189:1839–1845

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, Johnson R, Karin M (1999) Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science 284:316–320

    CAS  PubMed  Google Scholar 

  96. Gerondakis S, Grumont R, Gugasyan R, Wong L, Isomura I, Ho W, Banerjee A (2006) Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene 25:6781–6799

    CAS  PubMed  Google Scholar 

  97. Tanaka M, Fuentes ME, Yamaguchi K, Durnin MH, Dalrymple SA, Hardy KL, Goeddel DV (1999) Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity 10:421–429

    CAS  PubMed  Google Scholar 

  98. Senftleben U, Li ZW, Baud V, Karin M (2001) IKKbeta is essential for protecting T cells from TNFalpha-induced apoptosis. Immunity 14:217–230

    CAS  PubMed  Google Scholar 

  99. Takeda K et al (1999) Limb and skin abnormalities in mice lacking IKKα. Science 284:313–316

    CAS  PubMed  Google Scholar 

  100. Li Q, Lu Q, Hwang JY, Büscher D, Lee K-F, Izpisua-Belmonte JC, Verma IM (1999) IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev 13:1322–1328

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Solt LA, Madge LA, Orange JS, May MJ (2007) Interleukin-1-induced NF-κB activation is NEMO-dependent but does not require IKKβ. J Biol Chem 282:8724–8733

    PubMed Central  CAS  PubMed  Google Scholar 

  102. Schmidt-Supprian M, Bloch W, Courtois G, Addicks K, Israel A, Rajewsky K, Pasparakis M (2000) NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell 5:981–992

    CAS  PubMed  Google Scholar 

  103. Li Q, Estepa G, Memet S, Israel A, Verma IM (2000) Complete lack of NF-κB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev 14:1729–1733

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Hayden MS, Ghosh S (2012) NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26:203–234

    PubMed Central  CAS  PubMed  Google Scholar 

  105. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388:548–554

    CAS  PubMed  Google Scholar 

  106. Hacker H, Karin M (2006) Regulation and function of IKK and IKK-related kinases. Sci STKE 2006(357):re13

    PubMed  Google Scholar 

  107. Ling L, Cao Z, Goeddel DV (1998) NF-κB-inducing kinase activates IKK-α by phosphorylation of Ser-176. Proc Natl Acad Sci 95:3792–3797

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Regnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M (1997) Identification and characterization of an IkappaB kinase. Cell 90:373–383

    CAS  PubMed  Google Scholar 

  109. Xu G, Lo YC, Li Q, Napolitano G, Wu X, Jiang X, Dreano M, Karin M, Wu H (2011) Crystal structure of inhibitor of kappaB kinase beta. Nature 472:325–330

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18:2195–2224

    CAS  PubMed  Google Scholar 

  111. Tang ED, Inohara N, Wang C-Y, Nuñez G, Guan K-L (2003) Roles for homotypic interactions and transautophosphorylation in IκB kinase (IKKβ) activation. J Biol Chem 278:38566–38570

    CAS  PubMed  Google Scholar 

  112. Poyet J-L, Srinivasula SM, J-h L, Fernandes-Alnemri T, Yamaoka S, Tsichlis PN, Alnemri ES (2000) Activation of the IκB kinases by RIP via IKKγ/NEMO-mediated oligomerization. J Biol Chem 275:37966–37977

    CAS  PubMed  Google Scholar 

  113. Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, Ogura Y, Núñez G (2000) An induced proximity model for NF-κB activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem 275:27823–27831

    CAS  PubMed  Google Scholar 

  114. Wertz IE, Dixit VM (2010) Signaling to NF-kappaB: regulation by ubiquitination. Cold Spring Harb Perspect Biol 2:a003350

    PubMed Central  PubMed  Google Scholar 

  115. Chen J, Chen ZJ (2013) Regulation of NF-kappaB by ubiquitination. Curr Opin Immunol 25:4–12

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Finley D, Ozkaynak E, Varshavsky A (1987) The yeast polyubiquitin gene is essential for resistance to high temperatures, starvation, and other stresses. Cell 48:1035–1046

    CAS  PubMed  Google Scholar 

  117. Liu S, Chen ZJ (2011) Expanding role of ubiquitination in NF-[kappa]B signaling. Cell Res 21:6–21

    PubMed Central  PubMed  Google Scholar 

  118. Schwartz AL, Ciechanover A (2009) Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol 49:73–96

    CAS  PubMed  Google Scholar 

  119. Vallabhapurapu S, Karin M (2009) Regulation and function of NF-κB transcription factors in the immune system. Annu Rev Immunol 27:693–733

    CAS  PubMed  Google Scholar 

  120. Hurley JH, Lee S, Prag G (2006) Ubiquitin-binding domains. Biochem J 399:361–372

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Hicke L, Schubert HL, Hill CP (2005) Ubiquitin-binding domains. Nat Rev Mol Cell Biol 6:610–621

    CAS  PubMed  Google Scholar 

  122. Ikeda F, Dikic I (2008) Atypical ubiquitin chains: new molecular signals. “Protein modifications: beyond the usual suspects” review series. EMBO Rep 9:536–542

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Pickart CM, Fushman D (2004) Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol 8:610–616

    CAS  PubMed  Google Scholar 

  124. Chen ZJ, Sun LJ (2009) Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 33:275–286

    CAS  PubMed  Google Scholar 

  125. Skaug B, Jiang X, Chen ZJ (2009) The role of ubiquitin in NF-κB regulatory pathways. Annu Rev Biochem 78:769–796

    CAS  PubMed  Google Scholar 

  126. Reyes-Turcu FE, Wilkinson KD (2009) Polyubiquitin binding and disassembly by deubiquitinating enzymes. Chem Rev 109:1495–1508

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A (2000) Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 289:2350–2354

    PubMed Central  CAS  PubMed  Google Scholar 

  128. Compagno M et al (2009) Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 459:717–721

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Kato M et al (2009) Frequent inactivation of A20 in B-cell lymphomas. Nature 459:712–716

    CAS  PubMed  Google Scholar 

  130. Novak U et al (2009) The NF-κB negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas. Blood 113:4918–4921

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Schmitz R et al (2009) TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 206:981–989

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Musone SL et al (2008) Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet 40:1062–1064

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Sun SC (2010) CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes. Cell Death Differ 17:25–34

    CAS  PubMed  Google Scholar 

  134. Hershko A (1983) Ubiquitin: roles in protein modification and breakdown. Cell 34:11–12

    CAS  PubMed  Google Scholar 

  135. Pickart CM (2001) Ubiquitin enters the new millennium. Mol Cell 8:499–504

    CAS  PubMed  Google Scholar 

  136. Ciechanover A, Finley D, Varshavsky A (1984) Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell 37:57–66

    CAS  PubMed  Google Scholar 

  137. Finley D, Ciechanover A, Varshavsky A (1984) Thermolability of ubiquitin-activating enzyme from the mammalian cell cycle mutant ts85. Cell 37:43–55

    CAS  PubMed  Google Scholar 

  138. Pomerantz JL, Baltimore D (2002) Two pathways to NF-kappaB. Mol Cell 10:693–695

    CAS  PubMed  Google Scholar 

  139. Maniatis T (1999) A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev 13:505–510

    CAS  PubMed  Google Scholar 

  140. Lin L, Ghosh S (1996) A glycine-rich region in NF-kappaB p105 functions as a processing signal for the generation of the p50 subunit. Mol Cell Biol 16:2248–2254

    PubMed Central  CAS  PubMed  Google Scholar 

  141. Piwko W, Jentsch S (2006) Proteasome-mediated protein processing by bidirectional degradation initiated from an internal site. Nat Struct Mol Biol 13:691–697

    CAS  PubMed  Google Scholar 

  142. McKenzie FR, Connelly MA, Balzarano D, Muller JR, Geleziunas R, Marcu KB (2000) Functional isoforms of IkappaB kinase alpha (IKKalpha) lacking leucine zipper and helix-loop-helix domains reveal that IKKalpha and IKKbeta have different activation requirements. Mol Cell Biol 20:2635–2649

    PubMed Central  CAS  PubMed  Google Scholar 

  143. Agou F, Ye F, Goffinont S, Courtois G, Yamaoka S, Israël A, Véron M (2002) NEMO trimerizes through its coiled-coil C-terminal domain. J Biol Chem 277:17464–17475

    CAS  PubMed  Google Scholar 

  144. Tegethoff S, Behlke J, Scheidereit C (2003) Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation. Mol Cell Biol 23:2029–2041

    PubMed Central  CAS  PubMed  Google Scholar 

  145. Drew D, Shimada E, Huynh K, Bergqvist S, Talwar R, Karin M, Ghosh G (2007) Inhibitor kappaB kinase beta binding by inhibitor kappaB kinase gamma. Biochemistry 46:12482–12490

    CAS  PubMed  Google Scholar 

  146. Agou F, Traincard F, Vinolo E, Courtois G, Yamaoka S, Israël A, Véron M (2004) The trimerization domain of NEMO is composed of the interacting C-terminal CC2 and LZ coiled-coil subdomains. J Biol Chem 279:27861–27869

    CAS  PubMed  Google Scholar 

  147. Poyet J-L, Srinivasula SM, Alnemri ES (2001) vCLAP, a caspase-recruitment domain-containing protein of equine Herpesvirus-2, persistently activates the IκB kinases through oligomerization of IKKγ. J Biol Chem 276:3183–3187

    CAS  PubMed  Google Scholar 

  148. Huang GJ, Zhang ZQ, Jin DY (2002) Stimulation of IKK-gamma oligomerization by the human T-cell leukemia virus oncoprotein Tax. FEBS Lett 531:494–498

    CAS  PubMed  Google Scholar 

  149. Hofmann RM, Pickart CM (2001) In vitro assembly and recognition of Lys-63 polyubiquitin chains. J Biol Chem 276:27936–27943

    CAS  PubMed  Google Scholar 

  150. Xu P et al (2009) Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 137:133–145

    PubMed Central  CAS  PubMed  Google Scholar 

  151. Chen ZJ (2012) Ubiquitination in signaling to and activation of IKK. Immunol Rev 246:95–106

    PubMed Central  PubMed  Google Scholar 

  152. 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 TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351–361

    CAS  PubMed  Google Scholar 

  153. Hofmann RM, Pickart CM (1999) Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96:645–653

    CAS  PubMed  Google Scholar 

  154. Lomaga MA et al (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13:1015–1024

    PubMed Central  CAS  PubMed  Google Scholar 

  155. Naito A et al (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4:353–362

    CAS  PubMed  Google Scholar 

  156. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ (2006) Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 22:245–257

    CAS  PubMed  Google Scholar 

  157. Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD (2006) Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat Cell Biol 8:398–406

    CAS  PubMed  Google Scholar 

  158. Zhou H, Wertz I, O’Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM (2004) Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 427:167–171

    CAS  PubMed  Google Scholar 

  159. Ni CY et al (2008) Cutting edge: K63-linked polyubiquitination of NEMO modulates TLR signaling and inflammation in vivo. J Immunol 180:7107–7111

    PubMed Central  CAS  PubMed  Google Scholar 

  160. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412:346–351

    CAS  PubMed  Google Scholar 

  161. Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ (2009) Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 461:114–119

    PubMed Central  CAS  PubMed  Google Scholar 

  162. Shim J-H et al (2005) TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19:2668–2681

    PubMed Central  CAS  PubMed  Google Scholar 

  163. Chen ZJ, Bhoj V, Seth RB (2006) Ubiquitin, TAK1 and IKK: is there a connection? Cell Death Differ 13:687–692

    CAS  PubMed  Google Scholar 

  164. Oeckinghaus A, Wegener E, Welteke V, Ferch U, Arslan SC, Ruland J, Scheidereit C, Krappmann D (2007) Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. EMBO J 26:4634–4645

    PubMed Central  CAS  PubMed  Google Scholar 

  165. 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

    PubMed Central  CAS  PubMed  Google Scholar 

  166. Grivennikov SI, Karin M (2010) Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 20:65–71

    PubMed Central  CAS  PubMed  Google Scholar 

  167. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651

    PubMed Central  PubMed  Google Scholar 

  168. Staudt LM (2010) Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol 2:a000109

    PubMed Central  PubMed  Google Scholar 

  169. Ruland J (2011) Return to homeostasis: downregulation of NF-[kappa]B responses. Nat Immunol 12:709–714

    CAS  PubMed  Google Scholar 

  170. Arenzana-Seisdedos F, Thompson J, Rodriguez MS, Bachelerie F, Thomas D, Hay RT (1995) Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B. Mol Cell Biol 15:2689–2696

    PubMed Central  CAS  PubMed  Google Scholar 

  171. Peng B et al (2010) Defective feedback regulation of NF-kappaB underlies Sjogren’s syndrome in mice with mutated kappaB enhancers of the IkappaBalpha promoter. Proc Natl Acad Sci U S A 107:15193–15198

    PubMed Central  CAS  PubMed  Google Scholar 

  172. Ghosh S, Hayden MS (2012) Celebrating 25 years of NF-kappaB research. Immunol Rev 246:5–13

    PubMed Central  PubMed  Google Scholar 

  173. Rao P et al (2010) IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response. Nature 466:1115–1119

    PubMed Central  CAS  PubMed  Google Scholar 

  174. Scheibel M, Klein B, Merkle H, Schulz M, Fritsch R, Greten FR, Arkan MC, Schneider G, Schmid RM (2010) IkappaBbeta is an essential co-activator for LPS-induced IL-1beta transcription in vivo. J Exp Med 207:2621–2630

    PubMed Central  CAS  PubMed  Google Scholar 

  175. Phillips RJ, Ghosh S (1997) Regulation of IkappaB beta in WEHI 231 mature B cells. Mol Cell Biol 17:4390–4396

    PubMed Central  CAS  PubMed  Google Scholar 

  176. Weil R, Laurent-Winter C, Israël A (1997) Regulation of IκBβ degradation. Similarities to and differences from IκBα. J Biol Chem 272:9942–9949

    CAS  PubMed  Google Scholar 

  177. Bergqvist S, Alverdi V, Mengel B, Hoffmann A, Ghosh G, Komives EA (2009) Kinetic enhancement of NF-kappaBxDNA dissociation by IkappaBalpha. Proc Natl Acad Sci U S A 106:19328–19333

    PubMed Central  CAS  PubMed  Google Scholar 

  178. Tran K, Merika M, Thanos D (1997) Distinct functional properties of IkappaB alpha and IkappaB beta. Mol Cell Biol 17:5386–5399

    PubMed Central  CAS  PubMed  Google Scholar 

  179. Malek S, Huang D-B, Huxford T, Ghosh S, Ghosh G (2003) X-ray crystal structure of an IκBβ · NF-κB p65 homodimer complex. J Biol Chem 278:23094–23100

    CAS  PubMed  Google Scholar 

  180. Mahoney DJ et al (2008) Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci U S A 105:11778–11783

    PubMed Central  CAS  PubMed  Google Scholar 

  181. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384

    CAS  PubMed  Google Scholar 

  182. Rawlings DJ, Sommer K, Moreno-Garcia ME (2006) The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat Rev Immunol 6:799–812

    CAS  PubMed  Google Scholar 

  183. Wertz IE et al (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430:694–699

    CAS  PubMed  Google Scholar 

  184. Newton K et al (2008) Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies. Cell 134:668–678

    CAS  PubMed  Google Scholar 

  185. Heyninck K, Beyaert R (2005) A20 inhibits NF-kappaB activation by dual ubiquitin-editing functions. Trends Biochem Sci 30:1–4

    CAS  PubMed  Google Scholar 

  186. Boone DL et al (2004) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5:1052–1060

    CAS  PubMed  Google Scholar 

  187. Vereecke L, Beyaert R, van Loo G (2009) The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol 30:383–391

    CAS  PubMed  Google Scholar 

  188. Opipari AW Jr, Boguski MS, Dixit VM (1990) The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein. J Biol Chem 265:14705–14708

    CAS  PubMed  Google Scholar 

  189. 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 265:2973–2978

    CAS  PubMed  Google Scholar 

  190. Evans PC, Ovaa H, Hamon M, Kilshaw PJ, Hamm S, Bauer S, Ploegh HL, Smith TS (2004) Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity. Biochem J 378:727–734

    PubMed Central  CAS  PubMed  Google Scholar 

  191. Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R, Formisano S, Vito P, Leonardi A (2006) ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem 281:18482–18488

    CAS  PubMed  Google Scholar 

  192. Hitotsumatsu O et al (2008) The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity 28:381–390

    PubMed Central  CAS  PubMed  Google Scholar 

  193. Duwel M et al (2009) A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains. J Immunol 182:7718–7728

    PubMed  Google Scholar 

  194. Song HY, Rothe M, Goeddel DV (1996) The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci U S A 93:6721–6725

    PubMed Central  CAS  PubMed  Google Scholar 

  195. Komander D, Barford D (2008) Structure of the A20 OTU domain and mechanistic insights into deubiquitination. Biochem J 409:77–85

    CAS  PubMed  Google Scholar 

  196. Lin SC, Chung JY, Lamothe B, Rajashankar K, Lu M, Lo YC, Lam AY, Darnay BG, Wu H (2008) Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20. J Mol Biol 376:526–540

    PubMed Central  CAS  PubMed  Google Scholar 

  197. Enesa K, Zakkar M, Chaudhury H, Luong LA, Rawlinson L, Mason JC, Haskard DO, Dean JLE, Evans PC (2008) NF-κB suppression by the deubiquitinating enzyme cezanne: a novel negative feedback loop in pro-inflammatory signaling. J Biol Chem 283:7036–7045

    CAS  PubMed  Google Scholar 

  198. Bremm A, Freund SM, Komander D (2010) Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat Struct Mol Biol 17:939–947

    PubMed Central  CAS  PubMed  Google Scholar 

  199. 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

    CAS  PubMed  Google Scholar 

  200. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424:801–805

    CAS  PubMed  Google Scholar 

  201. 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

    CAS  PubMed  Google Scholar 

  202. 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

    PubMed Central  CAS  PubMed  Google Scholar 

  203. Reiley WW et al (2007) Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 204:1475–1485

    PubMed Central  CAS  PubMed  Google Scholar 

  204. Komander D, Reyes-Turcu F, Licchesi JD, Odenwaelder P, Wilkinson KD, Barford D (2009) Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep 10:466–473

    PubMed Central  CAS  PubMed  Google Scholar 

  205. Komander D, Lord CJ, Scheel H, Swift S, Hofmann K, Ashworth A, Barford D (2008) The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell 29:451–464

    CAS  PubMed  Google Scholar 

  206. Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC (2006) Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7:411–417

    CAS  PubMed  Google Scholar 

  207. Sun SC (2008) Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8:501–511

    CAS  PubMed  Google Scholar 

  208. Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R (2006) Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 125:665–677

    CAS  PubMed  Google Scholar 

  209. 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

    PubMed Central  CAS  PubMed  Google Scholar 

  210. Jin W et al (2008) Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest 118:1858–1866

    PubMed Central  CAS  PubMed  Google Scholar 

  211. Jin W, Reiley WR, Lee AJ, Wright A, Wu X, Zhang M, Sun SC (2007) Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells. J Biol Chem 282:15884–15893

    CAS  PubMed  Google Scholar 

  212. Lee AJ, Zhou X, Chang M, Hunzeker J, Bonneau RH, Zhou D, Sun SC (2010) Regulation of natural killer T-cell development by deubiquitinase CYLD. EMBO J 29:1600–1612

    PubMed Central  CAS  PubMed  Google Scholar 

  213. Hovelmeyer N et al (2007) Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD. J Exp Med 204:2615–2627

    PubMed Central  PubMed  Google Scholar 

  214. Makris C, Godfrey VL, Krahn-Senftleben G, Takahashi T, Roberts JL, Schwarz T, Feng L, Johnson RS, Karin M (2000) Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 5:969–979

    CAS  PubMed  Google Scholar 

  215. Li H, Kobayashi M, Blonska M, You Y, Lin X (2006) Ubiquitination of RIP is required for tumor necrosis factor α-induced NF-κB activation. J Biol Chem 281:13636–13643

    CAS  PubMed  Google Scholar 

  216. Xu M, Skaug B, Zeng W, Chen ZJ (2009) A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFalpha and IL-1beta. Mol Cell 36:302–314

    PubMed Central  CAS  PubMed  Google Scholar 

  217. Fukushima T, S-i M, Kress CL, Bruey JM, Krajewska M, Lefebvre S, Zapata JM, Ze R, Reed JC (2007) Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses. Proc Natl Acad Sci 104:6371–6376

    PubMed Central  CAS  PubMed  Google Scholar 

  218. Yamamoto M et al (2006) Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol 7:962–970

    CAS  PubMed  Google Scholar 

  219. Yeh WC et al (1997) Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7:715–725

    CAS  PubMed  Google Scholar 

  220. Nakano H et al (1999) Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation. Proc Natl Acad Sci U S A 96:9803–9808

    PubMed Central  CAS  PubMed  Google Scholar 

  221. Tada K et al (2001) Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death. J Biol Chem 276:36530–36534

    CAS  PubMed  Google Scholar 

  222. Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, Inoue J (2001) Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J 20:1271–1280

    PubMed Central  CAS  PubMed  Google Scholar 

  223. Conze DB, Albert L, Ferrick DA, Goeddel DV, Yeh WC, Mak T, Ashwell JD (2005) Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo. Mol Cell Biol 25:3348–3356

    PubMed Central  CAS  PubMed  Google Scholar 

  224. Conte D, Holcik M, Lefebvre CA, Lacasse E, Picketts DJ, Wright KE, Korneluk RG (2006) Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival. Mol Cell Biol 26:699–708

    PubMed Central  CAS  PubMed  Google Scholar 

  225. Varfolomeev E, Vucic D (2008) (Un)expected roles of c-IAPs in apoptotic and NFkappaB signaling pathways. Cell Cycle 7:1511–1521

    CAS  PubMed  Google Scholar 

  226. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P (1998) The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity 8:297–303

    CAS  PubMed  Google Scholar 

  227. Gerlach B et al (2011) Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471:591–596

    CAS  PubMed  Google Scholar 

  228. Dynek JN et al (2010) c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling. EMBO J 29:4198–4209

    PubMed Central  CAS  PubMed  Google Scholar 

  229. Haas TL et al (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 36:831–844

    CAS  PubMed  Google Scholar 

  230. Mollah S, Wertz IE, Phung Q, Arnott D, Dixit VM, Lill JR (2007) Targeted mass spectrometric strategy for global mapping of ubiquitination on proteins. Rapid Commun Mass Spectrom 21:3357–3364

    CAS  PubMed  Google Scholar 

  231. Kim W et al (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 44:325–340

    PubMed Central  CAS  PubMed  Google Scholar 

  232. Wong WW, Gentle IE, Nachbur U, Anderton H, Vaux DL, Silke J (2010) RIPK1 is not essential for TNFR1-induced activation of NF-kappaB. Cell Death Differ 17:482–487

    CAS  PubMed  Google Scholar 

  233. Zhang H, Zhou X, McQuade T, Li J, Chan FK, Zhang J (2011) Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471:373–376

    PubMed Central  CAS  PubMed  Google Scholar 

  234. Ofengeim D, Yuan J (2013) Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol 14:727–736

    CAS  PubMed  Google Scholar 

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    Dr. Arnab De

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De, A. (2015). Immune Homeostasis: Activation and Downregulation of NF-κB. In: Ubiquitin Chains: Degradation and Beyond. Springer Theses. Springer, Cham. https://doi.org/10.1007/978-3-319-14965-3_1

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