A single NFκB system for both canonical and non-canonical signaling

Cell Research

Volumn 21, Issue 1, 2011, Pages 86-102

  Shih, Vincent Feng Sheng ^a   Tsui, Rachel ^a   Caldwell, Andrew ^a   Hoffmann, Alexander ^a  

^a University of California San Diego   (United States)

Author keywords

immune development; immune response; inflammation; mathematical model; NF B; signaling crosstalk

Indexed keywords

I KAPPA B KINASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INHIBITOR OF APOPTOSIS PROTEIN; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 2; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 3;

HUMAN; INFLAMMATION; METABOLISM; PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION;

HUMANS; I-KAPPA B KINASE; INFLAMMATION; INHIBITOR OF APOPTOSIS PROTEINS; NF-KAPPA B; SIGNAL TRANSDUCTION; TNF RECEPTOR-ASSOCIATED FACTOR 2; TNF RECEPTOR-ASSOCIATED FACTOR 3;

EID: 78650907445     PISSN: 10010602     EISSN: 17487838     Source Type: Journal    
DOI: 10.1038/cr.2010.161     Document Type: Review

References (110)

1. Basak S, Kim H, Kearns JD, et al. A fourth IkappaB protein within the NF-kappaB signaling module. Cell 2007; 128:369-381.
2. Savinova OV, Hoffmann A, Ghosh G. The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of highmolecular- weight heterogeneous complexes. Mol Cell 2009; 34:591-602.
3. Shih VF, Kearns JD, Basak S, et al. Kinetic control of negative feedback regulators of NF-kappaB/RelA determines their pathogen- and cytokine-receptor signaling specificity. Proc Natl Acad Sci USA 2009; 106:9619-9624.
4. Scheidereit C. IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene 2006; 25:6685-6705.
5. Rudolph D, Yeh WC, Wakeham A, et al. Severe liver degeneration and lack of NF-kappaB activation in NEMO/ IKKgamma-deficient mice. Genes Dev 2000; 14:854-862.
6. Li Q, Van Antwerp D, Mercurio F, Lee KF, Verma IM. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 1999; 284:321-325.
7. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 1995; 376:167-170.
8. Luedde T, Heinrichsdorff J, de Lorenzi R, et al. IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver. Proc Natl Acad Sci USA 2008; 105:9733-9738.
9. Beinke S, Robinson MJ, Hugunin M, Ley SC. Lipopolysaccharide activation of the TPL-2/MEK/extracellular signalregulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NFkappaB1 p105. Mol Cell Biol 2004; 24:9658-9667.
10. Delhase M, Hayakawa M, Chen Y, Karin M. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 1999; 284:309-313.
11. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 2006; 22:245-257.
12. Xu M, Skaug B, Zeng W, Chen ZJ. A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFalpha and IL-1beta. Mol Cell 2009; 36:302-314.
13. Poyet J-L, Srinivasula SM, Lin J-h, et al. Activation of the IκB kinases by RIP via IKKα/NEMO-mediated oligomerization. J Biol Chem 2000; 275:37966-37977.
14. Haas TL, Emmerich CH, Gerlach B, et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 2009; 36:831-844.
15. Tokunaga F, Sakata S, Saeki Y, et al. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 2009; 11:123-132.
16. Deng L, Wang C, Spencer E, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitinconjugating enzyme complex and a unique polyubiquitin chain. Cell 2000; 103:351-361.
17. Chen ZJ, Parent L, Maniatis T. Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 1996; 84:853-862.
18. Lamhamedi-Cherradi SE, Zheng S, Hilliard BA, et al. Transcriptional regulation of type I diabetes by NF-kappa B. J Immunol 2003; 171:4886-4892.
19. Mason NJ, Liou HC, Hunter CA. T cell-intrinsic expression of c-Rel regulates Th1 cell responses essential for resistance to Toxoplasma gondii. J Immunol 2004; 172:3704-3711.
20. Ouaaz F, Arron J, Zheng Y, Choi Y, Beg AA. Dendritic cell development and survival require distinct NF-kappaB subunits. Immunity 2002; 16:257-270.
21. Wang J, Wang X, Hussain S, et al. Distinct roles of different NF-kappa B subunits in regulating inflammatory and T cell stimulatory gene expression in dendritic cells. J Immunol 2007; 178:6777-6788.
22. Carrasco D, Cheng J, Lewin A, et al. Multiple hemopoietic defects and lymphoid hyperplasia in mice lacking the transcriptional activation domain of the c-Rel protein. J Exp Med 1998; 187:973-984.
23. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 1996; 274:782-784.
24. Doi TS, Marino MW, Takahashi T, et al. Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci USA 1999; 96:2994-2999.
25. Alcamo E, Mizgerd JP, Horwitz BH, et al. Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-kappa B in leukocyte recruitment. J Immunol 2001; 167:1592-1600.
26. Grossmann M, Metcalf D, Merryfull J, et al. The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc Natl Acad Sci USA 1999; 96:11848-11853.
27. Gugasyan R, Voss A, Varigos G, et al. The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms. Mol Cell Biol 2004; 24:5733-5745.
28. Senftleben U, Li ZW, Baud V, Karin M. IKKbeta is essential for protecting T cells from TNFalpha-induced apoptosis. Immunity 2001; 14:217-230.
29. Prendes M, Zheng Y, Beg AA. Regulation of developing B cell survival by RelA-containing NF-kappa B complexes. J Immunol 2003; 171:3963-3969.
30. Bonnard M, Mirtsos C, Suzuki S, et al. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB- dependent gene transcription. EMBO J 2000; 19:4976-4985.
31. Sanjabi S, Hoffmann A, Liou HC, Baltimore D, Smale ST. Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages. Proc Natl Acad Sci USA 2000; 97:12705-12710.
32. Hoffmann A, Leung TH, Baltimore D. Genetic analysis of NF-kappaB/Rel transcription factors defines functional specificities. EMBO J 2003; 22:5530-5539.
33. Leung TH, Hoffmann A, Baltimore D. One nucleotide in a kappaB site can determine cofactor specificity for NFkappaB dimers. Cell 2004; 118:453-464.
34. Sanjabi S, Williams KJ, Saccani S, et al. A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation. Genes Dev 2005; 19:2138-2151.
35. Chen-Park FE, Huang DB, Noro B, Thanos D, Ghosh G. The kappa B DNA sequence from the HIV long terminal repeat functions as an allosteric regulator of HIV transcription. J Biol Chem 2002; 277:24701-24708.
36. Beg AA, Sha WC, Bronson RT, Baltimore D. Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice. Genes Dev 1995; 9:2736-2746.
37. Peng B, Ling J, Lee AJ, et al. Defective feedback regulation of NF-kappaB underlies Sjogren's syndrome in mice with mutated kappaB enhancers of the IkappaBalpha promoter. Proc Natl Acad Sci USA 2010; 107:15193-15198.
38. Memet S, Laouini D, Epinat JC, et al. IkappaBepsilondeficient mice: reduction of one T cell precursor subspecies and enhanced Ig isotype switching and cytokine synthesis. J Immunol 1999; 163:5994-6005.
39. Samson SI, Memet S, Vosshenrich CA, et al. Combined deficiency in IkappaBalpha and IkappaBepsilon reveals a critical window of NF-kappaB activity in natural killer cell differentiation. Blood 2004; 103:4573-4580.
40. O'Dea EL, Barken D, Peralta RQ, et al. A homeostatic model of IkappaB metabolism to control constitutive NF-kappaB activity. Mol Syst Biol 2007; 3:111.
41. Bergqvist S, Alverdi V, Mengel B, et al. Kinetic enhance ment of NF-κB•DNA dissociation by IκBα. Proc Natl Acad Sci USA 2009; 106:19328-19333.
42. Wertz IE, O'Rourke KM, Zhou H, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NFkappaB signalling. Nature 2004; 430:694-699.
43. Werner SL, Kearns JD, Zadorozhnaya V, et al. Encoding NF-kappaB temporal control in response to TNF: distinct roles for the negative regulators IkappaBalpha and A20. Genes Dev 2008; 22:2093-2101.
44. Saccani S, Marazzi I, Beg AA, Natoli G. Degradation of promoter-bound p65/RelA is essential for the prompt termination of the nuclear factor kappaB response. J Exp Med 2004; 200:107-113.
45. Liu B, Yang R, Wong KA, et al. Negative regulation of NFkappaB signaling by PIAS1. Mol Cell Biol 2005; 25:1113-1123.
46. Tahk S, Liu B, Chernishof V, et al. Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation. Proc Natl Acad Sci USA 2007; 104:11643-11648.
47. Lawrence T, Bebien M, Liu GY, Nizet V, Karin M. IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 2005; 434:1138-1143.
48. Hoffmann A, Levchenko A, Scott ML, Baltimore D. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science 2002; 298:1241-1245.
49. Kearns JD, Basak S, Werner SL, Huang CS, Hoffmann A. IkappaBepsilon provides negative feedback to control NFkappaB oscillations, signaling dynamics, and inflammatory gene expression. J Cell Biol 2006; 173:659-664.
50. Nelson DE, Ihekwaba AE, Elliott M, et al. Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science 2004; 306:704-708.
51. Ashall L, Horton CA, Nelson DE, et al. Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription. Science 2009; 324:242-246.
52. Paszek P, Jackson DA, White MR. Oscillatory control of signalling molecules. Curr Opin Genet Dev 2010; doi:10.1016/ j.gde.2010.08.004.
53. Werner SL, Barken D, Hoffmann A. Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 2005; 309:1857-1861.
54. Covert MW, Leung TH, Gaston JE, Baltimore D. Achieving stability of lipopolysaccharide-induced NF-kappaB activation. Science 2005; 309:1854-1857.
55. Behar M, Hoffmann A. Understanding the temporal codes of intra-cellular signals. Curr Opin Genet Dev 2010 Oct 16; doi:10.1016/j.gde.2010.09.007
56. Mathes E, O'Dea EL, Hoffmann A, Ghosh G. NF-kappaB dictates the degradation pathway of IkappaBalpha. EMBO J 2008; 27:1357-1367.
57. Mathes E, Wang L, Komives E, Ghosh G. Flexible regions within I{kappa}B{alpha} create the ubiquitin-independent degradation signal. J Biol Chem 2010; 285:32927-36.
58. O'Dea EL, Kearns JD, Hoffmann A. UV as an amplifier rather than inducer of NF-kappaB activity. Mol Cell 2008; 30:632-641.
59. Claudio E, Brown K, Park S, Wang H, Siebenlist U. BAFFinduced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol 2002; 3:958-965.
60. Zarnegar BJ, Wang Y, Mahoney DJ, et al. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol 2008; 9:1371-1378.
61. Vallabhapurapu S, Matsuzawa A, Zhang W, et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat Immunol 2008; 9:1364-1370.
62. He JQ, Zarnegar B, Oganesyan G, et al. Rescue of TRAF3- null mice by p100 NF-kappa B deficiency. J Exp Med 2006; 203:2413-2418.
63. Liao G, Zhang M, Harhaj EW, Sun SC. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor- associated factor 3-induced degradation. J Biol Chem 2004; 279:26243-26250.
64. Senftleben U, Cao Y, Xiao G, et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 2001; 293:1495-1499.
65. Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 2001; 7:401-409.
66. Xiao G, Fong A, Sun SC. Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation. J Biol Chem 2004; 279:30099-30105.
67. Mordmuller B, Krappmann D, Esen M, Wegener E, Scheidereit C. Lymphotoxin and lipopolysaccharide induce NF-kappaB-p52 generation by a co-translational mechanism. EMBO Rep 2003; 4:82-87.
68. Derudder E, Dejardin E, Pritchard LL, et al. RelB/p50 dimers are differentially regulated by tumor necrosis factor-alpha and lymphotoxin-beta receptor activation: critical roles for p100. J Biol Chem 2003; 278:23278-23284.
69. Fusco AJ, Savinova OV, Talwar R, et al. Stabilization of RelB requires multidomain interactions with p100/p52. J Biol Chem 2008; 283:12324-12332.
70. Basak S, Shih VF, Hoffmann A. Generation and activation of multiple dimeric transcription factors within the NF-kappaB signaling system. Mol Cell Biol 2008; 28:3139-3150.
71. Razani B, Zarnegar B, Ytterberg AJ, et al. Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation. Sci Signal 2010; 3:ra41.
72. Li T, Morgan MJ, Choksi S, et al. MicroRNAs modulate the noncanonical transcription factor NF-kappaB pathway by regulating expression of the kinase IKKalpha during macrophage differentiation. Nat Immunol 11:799-805.
73. Marienfeld R, Berberich-Siebelt F, Berberich I, et al. Signalspecific and phosphorylation-dependent RelB degradation: a potential mechanism of NF-kappaB control. Oncogene 2001; 20:8142-8147.
74. Weih F, Caamano J. Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol Rev 2003; 195:91-105.
75. Yilmaz ZB, Weih DS, Sivakumar V, Weih F. RelB is re quired for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF. EMBO J 2003; 22:121-130.
76. Yin L, Wu L, Wesche H, et al. Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIKdeficient mice. Science 2001; 291:2162-2165.
77. Shinkura R, Kitada K, Matsuda F, et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nfkappa b-inducing kinase. Nat Genet 1999; 22:74-77.
78. Fagarasan S, Shinkura R, Kamata T, et al. 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 2000; 191:1477-1486.
79. Caamano JH, Rizzo CA, Durham SK, et al. Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J Exp Med 1998; 187:185-196.
80. Franzoso G, Carlson L, Poljak L, et al. Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J Exp Med 1998; 187:147-159.
81. Weih DS, Yilmaz ZB, Weih F. Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J Immunol 2001; 167:1909-1919.
82. Cao Y, Bonizzi G, Seagroves TN, et al. IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 2001; 107:763-775.
83. Demicco EG, Kavanagh KT, Romieu-Mourez R, et al. RelB/p52 NF-kappaB complexes rescue an early delay in mammary gland development in transgenic mice with targeted suppressor IkappaB-alpha expression and promote carcinogenesis of the mammary gland. Mol Cell Biol 2005; 25:10136-10147.
84. Vaira S, Johnson T, Hirbe AC, et al. RelB is the NF-kappaB subunit downstream of NIK responsible for osteoclast differentiation. Proc Natl Acad Sci USA 2008; 105:3897-3902.
85. Wu L, D'Amico A, Winkel KD, et al. RelB is essential for the development of myeloid-related CD8alpha- dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells. Immunity 1998; 9:839-847.
86. Carrasco D, Ryseck RP, Bravo R. Expression of relB transcripts during lymphoid organ development: specific expression in dendritic antigen-presenting cells. Development 1993; 118:1221-1231.
87. Kobayashi T, Walsh PT, Walsh MC, et al. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 2003; 19:353-363.
88. Dejardin E, Droin NM, Delhase M, et al. The lymphotoxinbeta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 2002; 17:525-535.
89. Bonizzi G, Bebien M, Otero DC, et al. Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers. EMBO J 2004; 23:4202-4210.
90. Lovas A, Radke D, Albrecht D, et al. Differential RelA- and RelB-dependent gene transcription in LTbetaR-stimulated mouse embryonic fibroblasts. BMC Genomics 2008; 9:606.
91. Britanova LV, Makeev VJ, Kuprash DV. In vitro selection of optimal RelB/p52 DNA-binding motifs. Biochem Biophys Res Commun 2008; 365:583-588.
92. Sasaki Y, Derudder E, Hobeika E, et al. Canonical NF-kappaB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity 2006; 24:729-739.
93. Moorthy AK, Huang DB, Wang VY, Vu D, Ghosh G. X-ray structure of a NF-kappaB p50/RelB/DNA complex reveals assembly of multiple dimers on tandem kappaB sites. J Mol Biol 2007; 373:723-734.
94. Fusco AJ, Huang DB, Miller D, et al. NF-kappaB p52:RelB heterodimer recognizes two classes of kappaB sites with two distinct modes. EMBO Rep 2009; 10:152-159.
95. Pomerantz JL, Baltimore D. Two pathways to NF-kappaB. Mol Cell 2002; 10:693-695.
96. Mercurio F, DiDonato JA, Rosette C, Karin M. p105 and p98 precursor proteins play an active role in NF-kappa Bmediated signal transduction. Genes Dev 1993; 7:705-718.
97. Tucker E, O'Donnell K, Fuchsberger M, et al. A novel mutation in the Nfkb2 gene generates an NF-kappa B2 "super repressor". J Immunol 2007; 179:7514-7522.
98. Novack DV, Yin L, Hagen-Stapleton A, et al. The IkappaB function of NF-kappaB2 p100 controls stimulated osteoclastogenesis. J Exp Med 2003; 198:771-781.
99. Ishimaru N, Kishimoto H, Hayashi Y, Sprent J. Regulation of naive T cell function by the NF-kappaB2 pathway. Nat Immunol 2006; 7:763-772.
100. Courtois G, Gilmore TD. Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene 2006; 25:6831-6843.
101. Neri A, Fracchiolla NS, Migliazza A, Trecca D, Lombardi L. The involvement of the candidate proto-oncogene NFKB2/ lyt-10 in lymphoid malignancies. Leuk Lymphoma 1996; 23:43-48.
102. Annunziata CM, Davis RE, Demchenko Y, et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12:115-130.
103. Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007; 12:131-144.
104. Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 1997; 385:540-544.
105. Bren GD, Solan NJ, Miyoshi H, et al. Transcription of the RelB gene is regulated by NF-kappaB. Oncogene 2001; 20:7722-7733.
106. Liptay S, Schmid RM, Nabel EG, Nabel GJ. Transcriptional regulation of NF-kappa B2: evidence for kappa B-mediated positive and negative autoregulation. Mol Cell Biol 1994; 14:7695-7703.
107. Muller JR, Siebenlist U. Lymphotoxin beta receptor induces sequential activation of distinct NF-kappa B factors via separate signaling pathways. J Biol Chem 2003; 278:12006-12012.
108. Alcamo E, Hacohen N, Schulte LC, et al. Requirement for the NF-kappaB family member RelA in the development of secondary lymphoid organs. J Exp Med 2002; 195:233-244.
109. Lo JC, Basak S, James ES, et al. Coordination between NFkappaB family members p50 and p52 is essential for mediating LTbetaR signals in the development and organization of secondary lymphoid tissues. Blood 2006; 107:1048-1055.
110. Sha WC, Liou HC, Tuomanen EI, Baltimore D. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 1995; 80:321-330.