Advertisement

NF-κB, IκB, and IKK: Integral Components of Immune System Signaling

  • Maria Carmen Mulero
  • Tom Huxford
  • Gourisankar GhoshEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1172)

Abstract

The NF-κB (Nuclear Factor kappa B) transcription factor plays crucial roles in the regulation of numerous biological processes including development of the immune system, inflammation, and innate and adaptive immune responses. Control over the immune cell functions of NF-κB results from signaling through one of two different routes: the canonical and noncanonical NF-κB signaling pathways. Present at the end of both pathways are the proteins NF-κB, IκB, and the IκB kinase (IKK). These proteins work together to deliver the myriad outcomes that influence context-dependent transcriptional control in immune cells. In the present chapter, we review the structural information available on NF-κB, IκB, and IKK, the critical terminal components of the NF-κB signaling, in relation to their physiological function.

Keywords

NF-κB (nuclear factor κB) IκB (inhibitor of NF-κB) IKK (IκB kinase) Signal transduction Transcription factor 

Notes

Acknowledgements

Research is funded by the National Institutes of Health Grant GM085490 to GG. Biochemistry research at SDSU is supported in part by the California Metabolic Research Foundation.

References

  1. 1.
    Agou F, Ye F, Goffinont S, Courtois G, Yamaoka S, Isräel A, Veron M (2002) NEMO trimerizes through its coiled-coil C-terminal domain. J Biol Chem 277(20):17464–17475.  https://doi.org/10.1074/jbc.M201964200CrossRefPubMedGoogle Scholar
  2. 2.
    Bagneris C, Ageichik AV, Cronin N, Wallace B, Collins M, Boshoff C, Waksman G, Barrett T (2008) Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. Mol Cell 30(5):620–631.  https://doi.org/10.1016/j.molcel.2008.04.029CrossRefPubMedGoogle Scholar
  3. 3.
    Baltimore D, Beg AA (1995) DNA-binding proteins. A butterfly flutters by. Nature 373(6512):287–288.  https://doi.org/10.1038/373287a0CrossRefPubMedGoogle Scholar
  4. 4.
    Bergqvist S, Alverdi V, Mengel B, Hoffmann A, Ghosh G, Komives EA (2009) Kinetic enhancement of NF-κB:DNA dissociation by IκBα. Proc Natl Acad Sci USA 106(46):19328–19333.  https://doi.org/10.1073/pnas.0908797106CrossRefPubMedGoogle Scholar
  5. 5.
    Berkowitz B, Huang DB, Chen-Park FE, Sigler PB, Ghosh G (2002) The X-ray crystal structure of the NF-κB p50/p65 heterodimer bound to the interferonβ κB site. J Biol Chem 277(27):24694–24700.  https://doi.org/10.1074/jbc.M200006200CrossRefPubMedGoogle Scholar
  6. 6.
    Chen FE, Huang DB, Chen YQ, Ghosh G (1998) Crystal structure of p50/p65 heterodimer of transcription factor NF-κB bound to DNA. Nature 391(6665):410–413.  https://doi.org/10.1038/34956CrossRefGoogle Scholar
  7. 7.
    Chen YQ, Ghosh S, Ghosh G (1998) A novel DNA recognition mode by the NF-κB p65 homodimer. Nat Struct Biol 5(1):67–73CrossRefGoogle Scholar
  8. 8.
    Chen YQ, Sengchanthalangsy LL, Hackett A, Ghosh G (2000) NF-κB p65 (RelA) homodimer uses distinct mechanisms to recognize DNA targets. Structure 8(4):419–428CrossRefGoogle Scholar
  9. 9.
    Chen ZJ, Parent L, Maniatis T (1996) Site-specific phosphorylation of IκBα by a novel ubiquitination-dependent protein kinase activity. Cell 84(6):853–862CrossRefGoogle Scholar
  10. 10.
    Chen ZJ, Sun LJ (2009) Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 33(3):275–286.  https://doi.org/10.1016/j.molcel.2009.01.014CrossRefPubMedGoogle Scholar
  11. 11.
    Chen-Park FE, Huang DB, Noro B, Thanos D, Ghosh G (2002) The κB DNA sequence from the HIV long terminal repeat functions as an allosteric regulator of HIV transcription. J Biol Chem 277(27):24701–24708.  https://doi.org/10.1074/jbc.M200007200CrossRefPubMedGoogle Scholar
  12. 12.
    Cheng CS, Feldman KE, Lee J, Verma S, Huang DB, Huynh K, Chang M, Ponomarenko JV, Sun SC, Benedict CA, Ghosh G, Hoffmann A (2011) The specificity of innate immune responses is enforced by repression of interferon response elements by NF-κB p 50. Sci Signal 4(161):ra11.  https://doi.org/10.1126/scisignal.2001501CrossRefGoogle Scholar
  13. 13.
    Courtois G, Isräel A (2011) IKK regulation and human genetics. Curr Top Microbiol Immunol 349:73–95.  https://doi.org/10.1007/82_2010_98CrossRefPubMedGoogle Scholar
  14. 14.
    Cramer P, Larson CJ, Verdine GL, Müller CW (1997) Structure of the human NF-κB p 52 homodimer-DNA complex at 2.1 Å resolution. EMBO J 16(23):7078–7090.  https://doi.org/10.1093/emboj/16.23.7078CrossRefGoogle Scholar
  15. 15.
    Delhase M, Hayakawa M, Chen Y, Karin M (1999) Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation. Science 284(5412):309–313CrossRefGoogle Scholar
  16. 16.
    Dembinski HE, Wismer K, Vargas JD, Suryawanshi GW, Kern N, Kroon G, Dyson HJ, Hoffmann A, Komives EA (2017) Functional importance of stripping in NFκB signaling revealed by a stripping-impaired IκBα mutant. Proc Natl Acad Sci USA 114(8):1916–1921.  https://doi.org/10.1073/pnas.1610192114CrossRefPubMedGoogle Scholar
  17. 17.
    Escalante CR, Shen L, Thanos D, Aggarwal AK (2002) Structure of NF-κB p50/p65 heterodimer bound to the PRDII DNA element from the interferon-β promoter. Structure 10(3):383–391CrossRefGoogle Scholar
  18. 18.
    Fusco AJ, Huang DB, Miller D, Wang VY, Vu D, Ghosh G (2009) NF-κB p52:RelB heterodimer recognizes two classes of κB sites with two distinct modes. EMBO Rep 10(2):152–159.  https://doi.org/10.1038/embor.2008.227CrossRefPubMedGoogle Scholar
  19. 19.
    Ganchi PA, Sun SC, Greene WC, Ballard DW (1993) A novel NF-κB complex containing p65 homodimers: implications for transcriptional control at the level of subunit dimerization. Mol Cell Biol 13(12):7826–7835CrossRefGoogle Scholar
  20. 20.
    Ghosh G, van Duyne G, Ghosh S, Sigler PB (1995) Structure of NF-κB p50 homodimer bound to a κB site. Nature 373(6512):303–310.  https://doi.org/10.1038/373303a0CrossRefPubMedGoogle Scholar
  21. 21.
    Ghosh G, Wang VY, Huang DB, Fusco A (2012) NF-κB regulation: lessons from structures. Immunol Rev 246(1):36–58.  https://doi.org/10.1111/j.1600-065X.2012.01097.xCrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hatada EN, Nieters A, Wulczyn FG, Naumann M, Meyer R, Nucifora G, McKeithan TW, Scheidereit C (1992) The ankyrin repeat domains of the NF-κB precursor p105 and the protooncogene bcl-3 act as specific inhibitors of NF-κB DNA binding. Proc Natl Acad Sci USA 89(6):2489–2493CrossRefGoogle Scholar
  23. 23.
    Hayden MS, Ghosh S (2004) Signaling to NF-κB. Genes Dev 18(18):2195–2224.  https://doi.org/10.1101/gad.1228704CrossRefPubMedGoogle Scholar
  24. 24.
    Hayden MS, West AP, Ghosh S (2006) NF-κB and the immune response. Oncogene 25(51):6758–6780.  https://doi.org/10.1038/sj.onc.1209943CrossRefPubMedGoogle Scholar
  25. 25.
    Hoffmann A, Levchenko A, Scott ML, Baltimore D (2002) The IκB-NF-κB signaling module: temporal control and selective gene activation. Science 298(5596):1241–1245.  https://doi.org/10.1126/science.1071914CrossRefPubMedGoogle Scholar
  26. 26.
    Huang DB, Chen YQ, Ruetsche M, Phelps CB, Ghosh G (2001) X-ray crystal structure of proto-oncogene product c-Rel bound to the CD28 response element of IL-2. Structure 9(8):669–678CrossRefGoogle Scholar
  27. 27.
    Huang DB, Huxford T, Chen YQ, Ghosh G (1997) The role of DNA in the mechanism of NFκB dimer formation: crystal structures of the dimerization domains of the p50 and p65 subunits. Structure 5(11):1427–1436CrossRefGoogle Scholar
  28. 28.
    Huang DB, Vu D, Ghosh G (2005) NF-κB RelB forms an intertwined homodimer. Structure 13(9):1365–1373.  https://doi.org/10.1016/j.str.2005.06.018CrossRefPubMedGoogle Scholar
  29. 29.
    Huxford T, Ghosh G (2009) A structural guide to proteins of the NF-κB signaling module. Cold Spring Harb Perspect Biol 1(3):a000075.  https://doi.org/10.1101/cshperspect.a000075CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Huxford T, Hoffmann A, Ghosh G (2011) Understanding the logic of IκB:NF-κB regulation in structural terms. Curr Top Microbiol Immunol 349:1–24.  https://doi.org/10.1007/82_2010_99CrossRefPubMedGoogle Scholar
  31. 31.
    Huxford T, Huang DB, Malek S, Ghosh G (1998) The crystal structure of the IκBα/NF-κB complex reveals mechanisms of NF-κB inactivation. Cell 95(6):759–770CrossRefGoogle Scholar
  32. 32.
    Huxford T, Mishler D, Phelps CB, Huang DB, Sengchanthalangsy LL, Reeves R, Hughes CA, Komives EA, Ghosh G (2002) Solvent exposed non-contacting amino acids play a critical role in NF-κB/IκBα complex formation. J Mol Biol 324(4):587–597CrossRefGoogle Scholar
  33. 33.
    Isräel A (2010) The IKK complex, a central regulator of NF-κB activation. Cold Spring Harb Perspect Biol 2(3):a000158.  https://doi.org/10.1101/cshperspect.a000158CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Jacobs MD, Harrison SC (1998) Structure of an IκBα/NF-κB complex. Cell 95(6):749–758CrossRefGoogle Scholar
  35. 35.
    Leonardi A, Chariot A, Claudio E, Cunningham K, Siebenlist U (2000) CIKS, a connection to IκB kinase and stress-activated protein kinase. Proc Natl Acad Sci USA 97(19):10494–10499.  https://doi.org/10.1073/pnas.190245697CrossRefPubMedGoogle Scholar
  36. 36.
    Leung TH, Hoffmann A, Baltimore D (2004) One nucleotide in a κB site can determine cofactor specificity for NF-κB dimers. Cell 118(4):453–464.  https://doi.org/10.1016/j.cell.2004.08.007CrossRefPubMedGoogle Scholar
  37. 37.
    Liang C, Zhang M, Sun SC (2006) β-TrCP binding and processing of NF-κB2/p100 involve its phosphorylation at serines 866 and 870. Cell Signal 18(8):1309–1317.  https://doi.org/10.1016/j.cellsig.2005.10.011CrossRefPubMedGoogle Scholar
  38. 38.
    Liu S, Misquitta YR, Olland A, Johnson MA, Kelleher KS, Kriz R, Lin LL, Stahl M, Mosyak L (2013) Crystal structure of a human IκB kinase β asymmetric dimer. J Biol Chem 288(31):22758–22767.  https://doi.org/10.1074/jbc.M113.482596CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Malek S, Huang DB, Huxford T, Ghosh S, Ghosh G (2003) X-ray crystal structure of an IκBβ:NF-κB p65 homodimer complex. J Biol Chem 278(25):23094–23100.  https://doi.org/10.1074/jbc.M301022200CrossRefPubMedGoogle Scholar
  40. 40.
    Marienfeld R, Berberich-Siebelt F, Berberich I, Denk A, Serfling E, Neumann M (2001) Signal-specific and phosphorylation-dependent RelB degradation: a potential mechanism of NF-κB control. Oncogene 20(56):8142–8147.  https://doi.org/10.1038/sj.onc.1204884CrossRefPubMedGoogle Scholar
  41. 41.
    Marienfeld RB, Palkowitsch L, Ghosh S (2006) Dimerization of the IκB kinase-binding domain of NEMO is required for tumor necrosis factor α-induced NF-κB activity. Mol Cell Biol 26(24):9209–9219.  https://doi.org/10.1128/MCB.00478-06CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Martone R, Euskirchen G, Bertone P, Hartman S, Royce TE, Luscombe NM, Rinn JL, Nelson FK, Miller P, Gerstein M, Weissman S, Snyder M (2003) Distribution of NF-κB-binding sites across human chromosome 22. Proc Natl Acad Sci USA 100(21):12247–12252.  https://doi.org/10.1073/pnas.2135255100CrossRefPubMedGoogle Scholar
  43. 43.
    Mathes E, Wang L, Komives E, Ghosh G (2010) Flexible regions within IκBα create the ubiquitin-independent degradation signal. J Biol Chem 285(43):32927–32936.  https://doi.org/10.1074/jbc.M110.107326CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Mercurio F, Zhu H, Murray BW, Shevchenko A, Bennett BL, Li J, Young DB, Barbosa M, Mann M, Manning A, Rao A (1997) IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-κB activation. Science 278(5339):860–866CrossRefGoogle Scholar
  45. 45.
    Michel F, Soler-Lopez M, Petosa C, Cramer P, Siebenlist U, Müller CW (2001) Crystal structure of the ankyrin repeat domain of Bcl-3: a unique member of the IκB protein family. EMBO J 20(22):6180–6190.  https://doi.org/10.1093/emboj/20.22.6180CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mitchell S, Vargas J, Hoffmann A (2016) Signaling via the NFκB system. Wiley Interdiscip Rev Syst Biol Med 8(3):227–241.  https://doi.org/10.1002/wsbm.1331CrossRefPubMedGoogle Scholar
  47. 47.
    Moorthy AK, Huang DB, Wang VY, Vu D, Ghosh G (2007) X-ray structure of a NF-κB p50/RelB/DNA complex reveals assembly of multiple dimers on tandem κB sites. J Mol Biol 373(3):723–734.  https://doi.org/10.1016/j.jmb.2007.08.039CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Mulero MC, Shahabi S, Ko MS, Schiffer JM, Huang DB, Wang VY, Amaro RE, Huxford T, Ghosh G (2018) Protein cofactors are essential for high-affinity DNA binding by the nuclear factor κB RelA subunit. Biochemistry 57(20):2943–2957.  https://doi.org/10.1021/acs.biochem.8b00158CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Müller CW, Rey FA, Harrison SC (1996) Comparison of two different DNA-binding modes of the NF-κB p50 homodimer. Nat Struct Biol 3(3):224–227CrossRefGoogle Scholar
  50. 50.
    Müller CW, Rey FA, Sodeoka M, Verdine GL, Harrison SC (1995) Structure of the NF-κB p50 homodimer bound to DNA. Nature 373(6512):311–317.  https://doi.org/10.1038/373311a0CrossRefPubMedGoogle Scholar
  51. 51.
    Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (1999) The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398(6724):252–256.  https://doi.org/10.1038/18465CrossRefPubMedGoogle Scholar
  52. 52.
    Palkowitsch L, Leidner J, Ghosh S, Marienfeld RB (2008) Phosphorylation of serine 68 in the IκB kinase (IKK)-binding domain of NEMO interferes with the structure of the IKK complex and tumor necrosis factor-α-induced NF-κB activity. J Biol Chem 283(1):76–86.  https://doi.org/10.1074/jbc.M708856200CrossRefPubMedGoogle Scholar
  53. 53.
    Panne D, Maniatis T, Harrison SC (2007) An atomic model of the interferon-β enhanceosome. Cell 129(6):1111–1123.  https://doi.org/10.1016/j.cell.2007.05.019CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Phelps CB, Sengchanthalangsy LL, Huxford T, Ghosh G (2000) Mechanism of IκBα binding to NF-κB dimers. J Biol Chem 275(38):29840–29846.  https://doi.org/10.1074/jbc.M004899200CrossRefPubMedGoogle Scholar
  55. 55.
    Polley S, Huang DB, Hauenstein AV, Fusco AJ, Zhong X, Vu D, Schröfelbauer B, Kim Y, Hoffmann A, Verma IM, Ghosh G, Huxford T (2013) A structural basis for IκB kinase 2 activation via oligomerization-dependent trans auto-phosphorylation. PLoS Biol 11(6):e1001581.  https://doi.org/10.1371/journal.pbio.1001581CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Polley S, Passos DO, Huang DB, Mulero MC, Mazumder A, Biswas T, Verma IM, Lyumkis D, Ghosh G (2016) Structural basis for the activation of IKK1/α. Cell Rep 17(8):1907–1914.  https://doi.org/10.1016/j.celrep.2016.10.067CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Potoyan DA, Zheng W, Ferreiro DU, Wolynes PG, Komives EA (2016) PEST control of molecular stripping of NFκB from DNA transcription sites. J Phys Chem B 120(33):8532–8538.  https://doi.org/10.1021/acs.jpcb.6b02359CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, Kensche T, Uejima T, Bloor S, Komander D, Randow F, Wakatsuki S, Dikic I (2009) Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 136(6):1098–1109.  https://doi.org/10.1016/j.cell.2009.03.007CrossRefPubMedGoogle Scholar
  59. 59.
    Ramsey KM, Dembinski HE, Chen W, Ricci CG, Komives EA (2017) DNA and IκBα both induce long-range conformational changes in NFκB. J Mol Biol 429(7):999–1008.  https://doi.org/10.1016/j.jmb.2017.02.017CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Rushe M, Silvian L, Bixler S, Chen LL, Cheung A, Bowes S, Cuervo H, Berkowitz S, Zheng T, Guckian K, Pellegrini M, Lugovskoy A (2008) Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site. Structure 16(5):798–808.  https://doi.org/10.1016/j.str.2008.02.012CrossRefPubMedGoogle Scholar
  61. 61.
    Savinova OV, Hoffmann A, Ghosh G (2009) The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. Mol Cell 34(5):591–602.  https://doi.org/10.1016/j.molcel.2009.04.033CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Schuster M, Annemann M, Plaza-Sirvent C, Schmitz I (2013) Atypical IkappaB proteins—nuclear modulators of NF-κB signaling. Cell Commun Signal 11(1):23.  https://doi.org/10.1186/1478-811X-11-23CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Sen R, Baltimore D (1986) Inducibility of kappa immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 47(6):921–928CrossRefGoogle Scholar
  64. 64.
    Sen R, Baltimore D (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46(5):705–716CrossRefGoogle Scholar
  65. 65.
    Sengchanthalangsy LL, Datta S, Huang DB, Anderson E, Braswell EH, Ghosh G (1999) Characterization of the dimer interface of transcription factor NFκB p50 homodimer. J Mol Biol 289(4):1029–1040.  https://doi.org/10.1006/jmbi.1999.2823CrossRefPubMedGoogle Scholar
  66. 66.
    Shih VF, Kearns JD, Basak S, Savinova OV, Ghosh G, Hoffmann A (2009) Kinetic control of negative feedback regulators of NF-κB/RelA determines their pathogen- and cytokine-receptor signaling specificity. Proc Natl Acad Sci USA 106(24):9619–9624.  https://doi.org/10.1073/pnas.0812367106CrossRefPubMedGoogle Scholar
  67. 67.
    Shiina T, Konno A, Oonuma T, Kitamura H, Imaoka K, Takeda N, Todokoro K, Morimatsu M (2004) Targeted disruption of MAIL, a nuclear IκB protein, leads to severe atopic dermatitis-like disease. J Biol Chem 279(53):55493–55498.  https://doi.org/10.1074/jbc.M409770200CrossRefPubMedGoogle Scholar
  68. 68.
    Sil AK, Maeda S, Sano Y, Roop DR, Karin M (2004) IκB kinase-α acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428(6983):660–664.  https://doi.org/10.1038/nature02421CrossRefPubMedGoogle Scholar
  69. 69.
    Sue SC, Dyson HJ (2009) Interaction of the IκBα C-terminal PEST sequence with NF-κB: insights into the inhibition of NF-κB DNA binding by IκBα. J Mol Biol 388(4):824–838.  https://doi.org/10.1016/j.jmb.2009.03.048CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Sun SC (2017) The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol 17(9):545–558.  https://doi.org/10.1038/nri.2017.52CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Tao Z, Fusco A, Huang DB, Gupta K, Young Kim D, Ware CF, Van Duyne GD, Ghosh G (2014) p100/IκBdelta sequesters and inhibits NF-κB through kappaBsome formation. Proc Natl Acad Sci USA 111(45):15946–15951.  https://doi.org/10.1073/pnas.1408552111CrossRefPubMedGoogle Scholar
  72. 72.
    Tartey S, Matsushita K, Vandenbon A, Ori D, Imamura T, Mino T, Standley DM, Hoffmann JA, Reichhart JM, Akira S, Takeuchi O (2014) Akirin2 is critical for inducing inflammatory genes by bridging IκBζ and the SWI/SNF complex. EMBO J 33(20):2332–2348.  https://doi.org/10.15252/embj.201488447CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Tegethoff S, Behlke J, Scheidereit C (2003) Tetrameric oligomerization of IκB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-κB activation. Mol Cell Biol 23(6):2029–2041CrossRefGoogle Scholar
  74. 74.
    Trinh DV, Zhu N, Farhang G, Kim BJ, Huxford T (2008) The nuclear IκB protein IκBζ specifically binds NF-κB p50 homodimers and forms a ternary complex on κB DNA. J Mol Biol 379(1):122–135.  https://doi.org/10.1016/j.jmb.2008.03.060CrossRefPubMedGoogle Scholar
  75. 75.
    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.  https://doi.org/10.1038/35085597CrossRefPubMedGoogle Scholar
  76. 76.
    Xu G, Lo YC, Li Q, Napolitano G, Wu X, Jiang X, Dreano M, Karin M, Wu H (2011) Crystal structure of inhibitor of κB kinase β. Nature 472(7343):325–330.  https://doi.org/10.1038/nature09853CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Yamamoto M, Yamazaki S, Uematsu S, Sato S, Hemmi H, Hoshino K, Kaisho T, Kuwata H, Takeuchi O, Takeshige K, Saitoh T, Yamaoka S, Yamamoto N, Yamamoto S, Muta T, Takeda K, Akira S (2004) Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 430(6996):218–222.  https://doi.org/10.1038/nature02738CrossRefGoogle Scholar
  78. 78.
    Yamazaki S, Muta T, Takeshige K (2001) A novel IκB protein, IκBζ, induced by proinflammatory stimuli, negatively regulates nuclear factor-κB in the nuclei. J Biol Chem 276(29):27657–27662.  https://doi.org/10.1074/jbc.M103426200CrossRefPubMedGoogle Scholar
  79. 79.
    Yoshikawa A, Sato Y, Yamashita M, Mimura H, Yamagata A, Fukai S (2009) Crystal structure of the NEMO ubiquitin-binding domain in complex with Lys 63-linked di-ubiquitin. FEBS Lett 583(20):3317–3322.  https://doi.org/10.1016/j.febslet.2009.09.028CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Maria Carmen Mulero
    • 1
  • Tom Huxford
    • 2
  • Gourisankar Ghosh
    • 1
    Email author
  1. 1.Department of Chemistry & BiochemistryUniversity of California San DiegoLa JollaUSA
  2. 2.Structural Biochemistry Laboratory, Department of Chemistry & BiochemistrySan Diego State UniversitySan DiegoUSA

Personalised recommendations