The ubiquitination of NF-κB subunits in the control of transcription

Cells

Volumn 5, Issue 2, 2016, Pages

  Collins, Patricia E ^a   Mitxitorena, Izaskun ^a   Carmody, Ruaidhrí J ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

NF B; Transcription; Ubiquitination

Indexed keywords

I KAPPA B KINASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROTEIN P100; PROTEIN P105; SUPPRESSOR OF CYTOKINE SIGNALING 1; SYNAPTOTAGMIN I; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR; UBIQUITIN; UBIQUITIN PROTEIN LIGASE; UBIQUITIN PROTEIN LIGASE E3;

ACETYLATION; APOPTOSIS; GENE EXPRESSION; GENETIC TRANSCRIPTION; HERPES SIMPLEX VIRUS 1; HUMAN; IMMUNE RESPONSE; MASS SPECTROMETRY; NONHUMAN; PROTEIN DEGRADATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION; UBIQUITINATION;

EID: 85056746600     PISSN: None     EISSN: 20734409     Source Type: Journal    
DOI: 10.3390/cells5020023     Document Type: Review

References (204)

1. Schlesinger, D.H.; Goldstein, G.; Niall, H.D. Complete amino acid sequence of ubiquitin, an adenylate cyclase stimulating polypeptide probably universal in living cells. Biochemistry 1975, 14, 2214-2218
2. Goldstein, G.; Scheid, M.; Hammerling, U.; Schlesinger, D.H.; Niall, H.D.; Boyse, E.A. Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proc. Natl. Acad. Sci. USA 1975, 72, 11-15
3. Ciechanover, A.; Heller, H.; Elias, S.; Haas, A.L.; Hershko, A. Atp-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation. Proc. Natl. Acad. Sci. USA 1980, 77, 1365-1368
4. Hershko, A.; Ciechanover, A.; Heller, H.; Haas, A.L.; Rose, I.A. Proposed role of atp in protein breakdown: Conjugation of protein with multiple chains of the polypeptide of atp-dependent proteolysis. Proc. Natl. Acad. Sci. 1980, 77, 1783-1786
5. Wilkinson, K.D.; Urban, M.K.; Haas, A.L. Ubiquitin is the atp-dependent proteolysis factor i of rabbit reticulocytes. J. Biol. Chem. 1980, 255, 7529-7532
6. Bhoj, V.G.; Chen, Z.J. Ubiquitylation in innate and adaptive immunity. Nature 2009, 458, 430-437
7. Bergink, S.; Jentsch, S. Principles of ubiquitin and sumo modifications in DNA repair. Nature 2009, 458, 461-467
8. Muratani, M.; Tansey, W.P. How the ubiquitin-proteasome system controls transcription. Nat. Rev. Mol. Cell. Biol. 2003, 4, 192-201
9. Geng, F.; Wenzel, S.; Tansey, W.P. Ubiquitin and proteasomes in transcription. Annu. Rev. Biochem. 2012, 81, 177-201
10. Kaiser, P.; Flick, K.; Wittenberg, C.; Reed, S.I. Regulation of transcription by ubiquitination without proteolysis: Cdc34/scf(met30)-mediated inactivation of the transcription factor met4. Cell 2000, 102, 303-314
11. Hoppe, T.; Matuschewski, K.; Rape, M.; Schlenker, S.; Ulrich, H.D.; Jentsch, S. Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing. Cell 2000, 102, 577-586
12. Kanarek, N.; London, N.; Schueler-Furman, O.; Ben-Neriah, Y. Ubiquitination and degradation of the inhibitors of nf-κb. Cold Spring Harb. Perspect. Biol. 2010, 2
13. Archer, C.T.; Delahodde, A.; Gonzalez, F.; Johnston, S.A.; Kodadek, T. Activation domain-dependent monoubiquitylation of gal4 protein is essential for promoter binding in vivo. J. Biol. Chem. 2008, 283, 12614-12623
14. Wu, R.-C.; Feng, Q.; Lonard, D.M.; O’Malley, B.W. Src-3 coactivator functional lifetime is regulated by a phospho-dependent ubiquitin time clock. Cell 2007, 129, 1125-1140
15. Saccani, S.; Marazzi, I.; Beg, A.A.; 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
16. Zhang, Y. Transcriptional regulation by histone ubiquitination and deubiquitination. Genes Dev. 2003, 17, 2733-2740
17. Weake, V.M.; Workman, J.L. Histone ubiquitination: Triggering gene activity. Mol. Cell 2008, 29, 653-663
18. Molinari, E.; Gilman, M.; Natesan, S. Proteasome-mediated degradation of transcriptional activators correlates with activation domain potency in vivo. EMBO J. 1999, 18, 6439-6447
19. Salghetti, S.E.; Young Kim, S.; Tansey, W.P. Destruction of myc by ubiquitin-mediated proteolysis: Cancer-associated and transforming mutations stabilize myc. EMBO J. 1999, 18, 717-726
20. Salghetti, S.E.; Muratani, M.; Wijnen, H.; Futcher, B.; Tansey, W.P. Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis. Proc. Natl. Acad. Sci. USA 2000, 97, 3118-3123
21. Thomas, D.; Tyers, M. Transcriptional regulation: Kamikaze activators. Curr. Biol. 2000, 10, R341-R343
22. Conaway, R.C.; Brower, C.S.; Conaway, J.W. Emerging roles of ubiquitin in transcription regulation. Science 2002, 296, 1254-1258
23. Salghetti, S.E.; Caudy, A.A.; Chenoweth, J.G.; Tansey, W.P. Regulation of transcriptional activation domain function by ubiquitin. Science 2001, 293, 1651-1653
24. Lipford, J.R.; Deshaies, R.J. Diverse roles for ubiquitin-dependent proteolysis in transcriptional activation. Nat. Cell. Biol. 2003, 5, 845-850
25. Von der Lehr, N.; Johansson, S.; Wu, S.; Bahram, F.; Castell, A.; Cetinkaya, C.; Hydbring, P.; Weidung, I.; Nakayama, K.; Nakayama, K.I.; et al. The f-box protein skp2 participates in c-myc proteosomal degradation and acts as a cofactor for c-myc-regulated transcription. Mol. Cell 2003, 11, 1189-1200
26. Kim, S.Y.; Herbst, A.; Tworkowski, K.A.; Salghetti, S.E.; Tansey, W.P. Skp2 regulates myc protein stability and activity. Mol. Cell 2003, 11, 1177-1188
27. Perkins, N.D. Post-translational modifications regulating the activity and function of the nuclear factor kappa b pathway. Oncogene 2000, 25, 6717-6730
28. Moreno, R.; Sobotzik, J.-M.; Schultz, C.; Schmitz, M.L. Specification of the nf-κb transcriptional response by p65 phosphorylation and tnf-induced nuclear translocation of ikkε. Nucleic Acids Res. 2010, 38, 6029-6044
29. Smale, S.T. Hierarchies of nf-[kappa]b target-gene regulation. Nat. Immunol. 2011, 12, 689-694
30. Wertz, I.E.; Dixit, V.M. Signaling to NF-κB: Regulation by ubiquitination. Cold Spring Harb. Perspect. Biol. 2010, 2, a003350
31. Skaug, B.; Jiang, X.; Chen, Z.J. The role of ubiquitin in nf-kappab regulatory pathways. Annu. Rev. Biochem. 2009, 78, 769-796
32. Iwai, K. Diverse ubiquitin signaling in nf-kappab activation. Trends Cell Biol. 2012, 22, 355-364
33. Kanarek, N.; Ben-Neriah, Y. Regulation of nf-kappab by ubiquitination and degradation of the ikappabs. Immunol. Rev. 2012, 246, 77-94
34. Gilmore, T. Target genes of nf-kb. Available online: http://www.bu.edu/nf-kb/gene-resources/target-genes/.
35. DiDonato, J.A.; Mercurio, F.; Karin, M. Nf-κb and the link between inflammation and cancer. Immunol. Rev. 2012, 246, 379-400
36. Hayden, M.S.; Ghosh, S. Nf-κb, the first quarter-century: Remarkable progress and outstanding questions. Genes Dev. 2012, 26, 203-234
37. Baeuerle, P.; Baltimore, D. I kappa b: A specific inhibitor of the nf-kappa b transcription factor. Science 1988, 242, 540-546
38. Baeuerle, P.A.; Baltimore, D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the nf-κb transcription factor. Cell 1988, 53, 211-217
39. Beg, A.A.; Ruben, S.M.; Scheinman, R.I.; Haskill, S.; Rosen, C.A.; Baldwin, A.S. I kappa b interacts with the nuclear localization sequences of the subunits of nf-kappa b: A mechanism for cytoplasmic retention. Genes Dev. 1992, 6, 1899-1913
40. Johnson, C.; Van Antwerp, D.; Hope, T.J. An n-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of i[kappa]b[alpha]. EMBO J. 1999, 18, 6682-6693
41. Rodriguez, M.S.; Thompson, J.; Hay, R.T.; Dargemont, C. Nuclear retention of iκbα protects it from signal-induced degradation and inhibits nuclear factor κb transcriptional activation. J. Biol. Chem. 1999, 274, 9108-9115
42. Huang, T.T.; Kudo, N.; Yoshida, M.; Miyamoto, S. A nuclear export signal in the n-terminal regulatory domain of iκbα controls cytoplasmic localization of inactive nf-κb/iκbα complexes. Proc. Natl. Acad. Sci. USA 2000, 97, 1014-1019
43. Tam, W.F.; Lee, L.H.; Davis, L.; Sen, R. Cytoplasmic sequestration of rel proteins by iκbα requires crm1-dependent nuclear export. Mol. Cell. Biol. 2000, 20, 2269-2284
44. Ghosh, S.; Karin, M. Missing pieces in the nf-κb puzzle. Cell 2002, 109, S81-S96
45. Mercurio, F.; Zhu, H.; Murray, B.W.; Shevchenko, A.; Bennett, B.L.; Li, J.W.; Young, D.B.; Barbosa, M.; Mann, M.; Manning, A.; et al. Ikk-1 and ikk-2: Cytokine-activated iκb kinases essential for nf-κb activation. Science 1997, 278, 860-866
46. DiDonato, J.A.; Hayakawa, M.; Rothwarf, D.M.; Zandi, E.; Karin, M. A cytokine-responsive i[kappa]b kinase that activates the transcription factor nf-[kappa]b. Nature 1997, 388, 548-554
47. Rothwarf, D.M.; Zandi, E.; Natoli, G.; Karin, M. Ikk-[gamma] is an essential regulatory subunit of the i[kappa]b kinase complex. Nature 1998, 395, 297-300
48. Fuchs, S.Y.; Spiegelman, V.S.; Suresh Kumar, K.G. The many faces of [beta]-trcp e3 ubiquitin ligases: Reflections in the magic mirror of cancer. Oncogene 2000, 23, 2028-2036
49. Wu, G.; Xu, G.; Schulman, B.A.; Jeffrey, P.D.; Harper, J.W.; Pavletich, N.P. Structure of a β-trcp1-skp1-β-catenin complex: Destruction motif binding and lysine specificity of the scfβ-trcp1 ubiquitin ligase. Mol. Cell 2003, 11, 1445-1456
50. Alkalay, I.; Yaron, A.; Hatzubai, A.; Orian, A.; Ciechanover, A.; Ben-Neriah, Y. Stimulation-dependent I kappa b alpha phosphorylation marks the nf-kappa b inhibitor for degradation via the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA 1995, 92, 10599-10603
51. Chen, Z.; Hagler, J.; Palombella, V.J.; Melandri, F.; Scherer, D.; Ballard, D.; Maniatis, T. Signal-induced site-specific phosphorylation targets i kappa b alpha to the ubiquitin-proteasome pathway. Genes Dev. 1995, 9, 1586-1597
52. Yaron, A.; Hatzubai, A.; Davis, M.; Lavon, I.; Amit, S.; Manning, A.M.; Andersen, J.S.; Mann, M.; Mercurio, F.; Ben-Neriah, Y. Identification of the receptor component of the i[kappa]b[alpha]-ubiquitin ligase. Nature 1998, 396, 590-594
53. Winston, J.T.; Strack, P.; Beer-Romero, P.; Chu, C.Y.; Elledge, S.J.; Harper, J.W. The scfβ-trcp-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in iκbα and β-catenin and stimulates iκbα ubiquitination in vitro. Genes Dev. 1999, 13, 270-283
54. Spencer, E.; Jiang, J.; Chen, Z.J. Signal-induced ubiquitination of iκbα by the f-box protein slimb/β-trcp. Genes Dev. 1999, 13, 284-294
55. Hake, S.B.; Allis, C.D. Histone h3 variants and their potential role in indexing mammalian genomes: The “h3 barcode hypothesis”. Proc. Natl. Acad. Sci. USA 2006, 103, 6428-6435
56. Bosisio, D.; Marazzi, I.; Agresti, A.; Shimizu, N.; Bianchi, M.E.; Natoli, G. A hyper-dynamic equilibrium between promoter-bound and nucleoplasmic dimers controls nf-kappab-dependent gene activity. Embo J. 2006, 25, 798-810
57. Saccani, S.; Pantano, S.; Natoli, G. Modulation of nf-kappab activity by exchange of dimers. Mol. Cell 2003, 11, 1563-1574
58. Hoffmann, A.; Leung, T.H.; Baltimore, D. Genetic analysis of NF-κB/Rel transcription factors defines functional specificities. EMBO J. 2003, 22, 5530-5539
59. Lin, R.; Gewert, D.; Hiscott, J. Differential transcriptional activation in vitro by nf-b/rel proteins. J. Biol. Chem. 1995, 270, 3123-3131
60. Leung, T.H.; Hoffmann, A.; Baltimore, D. One nucleotide in a κb site can determine cofactor specificity for nf-κb dimers. Cell 2004, 118, 453-464
61. Gerondakis, S.; Grumont, R.; Gugasyan, R.; Wong, L.; Isomura, I.; Ho, W.; Banerjee, A. Unravelling the complexities of the nf-[kappa]b signalling pathway using mouse knockout and transgenic models. Oncogene 2000, 25, 6781-6799
62. Wiborg, O.; Pedersen, M.S.; Wind, A.; Berglund, L.E.; Marcker, K.A.; Vuust, J. The human ubiquitin multigene family: Some genes contain multiple directly repeated ubiquitin coding sequences. EMBO J. 1985, 4, 755-759
63. Redman, K.L.; Rechsteiner, M. Identification of the long ubiquitin extension as ribosomal protein s27a. Nature 1989, 338, 438-440
64. Heride, C.; Urbé, S.; Clague, M.J. Ubiquitin code assembly and disassembly. Curr. Biol. 2014, 24, R215-R220
65. Hershko, A.; Heller, H.; Elias, S.; Ciechanover, A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J. Biol. Chem. 1983, 258, 8206-8214
66. Kravtsova-Ivantsiv, Y.; Ciechanover, A. Non-canonical ubiquitin-based signals for proteasomal degradation. J. Cell Sci. 2012, 125, 539-548
67. Komander, D.; Rape, M. The ubiquitin code. Annu. Rev. Biochem. 2012, 81, 203-229
68. Berndsen, C.E.; Wolberger, C. New insights into ubiquitin e3 ligase mechanism. Nat. Struct. Mol. Biol. 2014, 21, 301-307
69. Metzger, M.B.; Hristova, V.A.; Weissman, A.M. Hect and ring finger families of e3 ubiquitin ligases at a glance. J. Cell Sci. 2012, 125, 531-537
70. Scheffner, M.; Kumar, S. Mammalian hect ubiquitin-protein ligases: Biological and pathophysiological aspects. Biochim. Biophys. Acta (BBA) Mol. Cell Rese. 2014, 1843, 61-74
71. Metzger, M.B.; Pruneda, J.N.; Klevit, R.E.; Weissman, A.M. Ring-type e3 ligases: Master manipulators of e2 ubiquitin-conjugating enzymes and ubiquitination. Biochim. Biophys. Acta (BBA) Mol. Cell Res. 2014, 1843, 47-60
72. Hua, Z.; Vierstra, R.D. The cullin-ring ubiquitin-protein ligases. Annu. Rev. Plant Biol. 2011, 62, 299-334
73. Komada, M. Controlling receptor downregulation by ubiquitination and deubiquitination. Curr. Drug Discov. Technol. 2008, 5, 78-84
74. Huang, O.W.; Cochran, A.G. Regulation of deubiquitinase proteolytic activity. Curr. Opin. Struct. Biol. 2013, 23, 806-811
75. Komander, D.; Clague, M.J.; Urbe, S. Breaking the chains: Structure and function of the deubiquitinases. Nat. Rev. Mol. Cell Biol. 2009, 10, 550-563
76. Eletr, Z.M.; Wilkinson, K.D. Regulation of proteolysis by human deubiquitinating enzymes. Biochim. Biophys. Acta (BBA) Mol. Cell Res. 2014, 1843, 114-128
77. Nijman, S.M.B.; Luna-Vargas, M.P.A.; Velds, A.; Brummelkamp, T.R.; Dirac, A.M.G.; Sixma, T.K.; Bernards, R. A genomic and functional inventory of deubiquitinating enzymes. Cell 2005, 123, 773-786
78. Colleran, A.; Collins, P.E.; O’Carroll, C.; Ahmed, A.; Mao, X.; McManus, B.; Kiely, P.A.; Burstein, E.; Carmody, R.J. Deubiquitination of nf-kappab by ubiquitin-specific protease-7 promotes transcription. Proc. Natl. Acad. Sci. USA 2013, 110, 618-623
79. Tzimas, C.; Michailidou, G.; Arsenakis, M.; Kieff, E.; Mosialos, G.; Hatzivassiliou, E.G. Human ubiquitin specific protease 31 is a deubiquitinating enzyme implicated in activation of nuclear factor-kappab. Cell. Signal. 2006, 18, 83-92
80. Schweitzer, K.; Naumann, M. Csn-associated usp48 confers stability to nuclear nf-kappab/rela by trimming k48-linked ub-chains. Biochim. Biophys. Acta 2015, 1853, 453-469
81. Kirisako, T.; Kamei, K.; Murata, S.; Kato, M.; Fukumoto, H.; Kanie, M.; Sano, S.; Tokunaga, F.; Tanaka, K.; Iwai, K. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 2006, 25, 4877-4887
82. Spence, J.; Sadis, S.; Haas, A.L.; Finley, D. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol. Cell. Biol. 1995, 15, 1265-1273
83. Ikeda, F.; Dikic, I. Atypical ubiquitin chains: New molecular signals. Protein modifications: Beyond the usual suspects review series. EMBO Rep. 2008, 9, 536-542
84. Kulathu, Y.; Komander, D. Atypical ubiquitylation-The unexplored world of polyubiquitin beyond lys48 and lys63 linkages. Nat. Rev. Mol. Cell Biol. 2012, 13, 508-523
85. Thrower, J.S.; Hoffman, L.; Rechsteiner, M.; Pickart, C.M. Recognition of the polyubiquitin proteolytic signal. EMBO J. 2000, 19, 94-102
86. Boutet, S.C.; Biressi, S.; Iori, K.; Natu, V.; Rando, T.A. Taf1 regulates pax3 protein by monoubiquitination in skeletal muscle progenitors. Mol. Cell 2010, 40, 749-761
87. Carvallo, L.; Muñoz, R.; Bustos, F.; Escobedo, N.; Carrasco, H.; Olivares, G.; Larraín, J. Non-canonical wnt signaling induces ubiquitination and degradation of syndecan4. J. Biol. Chem. 2010, 285, 29546-29555
88. Kravtsova-Ivantsiv, Y.; Cohen, S.; Ciechanover, A. Modification by single ubiquitin moieties rather than polyubiquitination is sufficient for proteasomal processing of the p105 nf-κb precursor. Mol. Cell 2009, 33, 496-504
89. Meyer, H.-J.; Rape, M. Enhanced protein degradation by branched ubiquitin chains. Cell 2014, 157, 910-921
90. Grice, G.L.; Lobb, I.T.; Weekes, M.P.; Gygi, S.P.; Antrobus, R.; Nathan, J.A. The proteasome distinguishes between heterotypic and homotypic lysine-11-linked polyubiquitin chains. Cell Rep. 2015, 12, 545-553.
91. Tanaka, T.; Grusby, M.J.; Kaisho, T. Pdlim2-mediated termination of transcription factor nf-kappab activation by intranuclear sequestration and degradation of the p65 subunit. Nat. Immunol. 2007, 8, 584-591
92. Lawrence, T.; Bebien, M.; Liu, G.Y.; Nizet, V.; Karin, M. Ikk[alpha] limits macrophage nf-[kappa]b activation and contributes to the resolution of inflammation. Nature 2005, 434, 1138-1143
93. Burstein, E.; Hoberg, J.E.; Wilkinson, A.S.; Rumble, J.M.; Csomos, R.A.; Komarck, C.M.; Maine, G.N.; Wilkinson, J.C.; Mayo, M.W.; Duckett, C.S. Commd proteins, a novel family of structural and functional homologs of murr1. J. Biol. Chem. 2005, 280, 22222-22232
94. Nozell, S.; Laver, T.; Moseley, D.; Nowoslawski, L.; DeVos, M.; Atkinson, G.P.; Harrison, K.; Nabors, L.B.; Benveniste, E.N. The ing4 tumor suppressor attenuates nf-κb activity at the promoters of target genes. Mol. Cell. Biol. 2008, 28, 6632-6645
95. Li, H.; Wittwer, T.; Weber, A.; Schneider, H.; Moreno, R.; Maine, G.N.; Kracht, M.; Schmitz, M.L.; Burstein, E. Regulation of nf-κb activity by competition between rela acetylation and ubiquitination. Oncogene 2012, 31, 611-623
96. Hochrainer, K.; Racchumi, G.; Zhang, S.; Iadecola, C.; Anrather, J. Monoubiquitination of nuclear rela negatively regulates nf-kappab activity independent of proteasomal degradation. Cell. Mol. Life Sci. CMLS 2012, 69, 2057-2073
97. Ea, C.K.; Baltimore, D. Regulation of nf-kappab activity through lysine monomethylation of p65. Proc. Natl. Acad. Sci. USA 2009, 106, 18972-18977
98. Yang, X.-D.; Tajkhorshid, E.; Chen, L.-F. Functional interplay between acetylation and methylation of the rela subunit of nf-κb. Mol. Cell. Biol. 2010, 30, 2170-2180
99. Yang, X.-D.; Huang, B.; Li, M.; Lamb, A.; Kelleher, N.L.; Chen, L.-F. Negative regulation of nf-κb action by set9-mediated lysine methylation of the rela subunit. EMBO J. 2009, 28, 1055-1066
100. Chen, L.-F.; Williams, S.A.; Mu, Y.; Nakano, H.; Duerr, J.M.; Buckbinder, L.; Greene, W.C. Nf-κb rela phosphorylation regulates rela acetylation. Mol. Cell. Biol. 2005, 25, 7966-7975
101. Buerki, C.; Rothgiesser, K.M.; Valovka, T.; Owen, H.R.; Rehrauer, H.; Fey, M.; Lane, W.S.; Hottiger, M.O. Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of rela/p65. Nucleic Acids Res. 2008, 36, 1665-1680
102. Geng, H.; Wittwer, T.; Dittrich-Breiholz, O.; Kracht, M.; Schmitz, M.L. Phosphorylation of nf-κb p65 at ser468 controls its commd1-dependent ubiquitination and target gene-specific proteasomal elimination. EMBO Rep. 2009, 10, 381-386
103. Mao, X.; Gluck, N.; Li, D.; Maine, G.N.; Li, H.; Zaidi, I.W.; Repaka, A.; Mayo, M.W.; Burstein, E. Gcn5 is a required cofactor for a ubiquitin ligase that targets nf-κb/rela. Genes Dev. 2009, 23, 849-861
104. Sasaki, C.Y.; Barberi, T.J.; Ghosh, P.; Longo, D.L. Phosphorylation of rela/p65 on serine 536 defines an i{kappa}b{alpha}-independent nf-{kappa}b pathway. J. Biol. Chem. 2005, 280, 34538-34547
105. Nolan, G.P.; Fujita, T.; Bhatia, K.; Huppi, C.; Liou, H.C.; Scott, M.L.; Baltimore, D. The bcl-3 proto-oncogene encodes a nuclear i kappa b-like molecule that preferentially interacts with nf-kappa b p50 and p52 in a phosphorylation-dependent manner. Mol. Cell Biol. 1993, 13, 3557-3566
106. Inoue, J.; Takahara, T.; Akizawa, T.; Hino, O. Bcl-3, a member of the i kappa b proteins, has distinct specificity towards the rel family of proteins. Oncogene 1993, 8, 2067-2073
107. Kerr, L.D.; Duckett, C.S.; Wamsley, P.; Zhang, Q.; Chiao, P.; Nabel, G.; McKeithan, T.W.; Baeuerle, P.A.; Verma, I.M. The proto-oncogene bcl-3 encodes an i kappa b protein. Genes Dev. 1992, 6, 2352-2363
108. McKeithan, T.W.; Rowley, J.D.; Shows, T.B.; Diaz, M.O. Cloning of the chromosome translocation breakpoint junction of the t(14;19) in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA 1987, 84, 9257-9260
109. Maldonado, V.; Melendez-Zajgla, J. Role of bcl-3 in solid tumors. Mol. Cancer 2011, 10, 1-7
110. Carmody, R.J.; Ruan, Q.; Palmer, S.; Hilliard, B.; Chen, Y.H. Negative regulation of toll-like receptor signaling by nf-κb p50 ubiquitination blockade. Science 2007, 317, 675-678
111. Riemann, M.; Endres, R.; Liptay, S.; Pfeffer, K.; Schmid, R.M. The iκb protein bcl-3 negatively regulates transcription of the il-10 gene in macrophages. J. Immunol. 2005, 175, 3560-3568
112. Collins, P.E.; Kiely, P.A.; Carmody, R.J. Inhibition of transcription by b cell leukemia 3 (bcl-3) protein requires interaction with nuclear factor kappab (nf-kappab) p50. J. Biol. Chem. 2014, 289, 7059-7067
113. Hailfinger, S.; Nogai, H.; Pelzer, C.; Jaworski, M.; Cabalzar, K.; Charton, J.-E.; Guzzardi, M.; Décaillet, C.; Grau, M.; Dörken, B.; et al. Malt1-dependent relb cleavage promotes canonical nf-κb activation in lymphocytes and lymphoma cell lines. Proc. Natl. Acad. Sci. USA 2011, 108, 14596-14601
114. Marienfeld, R.; Berberich-Siebelt, F.; Berberich, I.; Denk, A.; Serfling, E.; Neumann, M. Signal-specific and phosphorylation-dependent relb degradation: A potential mechanism of nf-kappab control. Oncogene 2001, 20, 8142-8147
115. Leidner, J.; Palkowitsch, L.; Marienfeld, U.; Fischer, D.; Marienfeld, R. Identification of lysine residues critical for the transcriptional activity and polyubiquitination of the nf-kappab family member relb. Biochem. J. 2008, 416, 117-127
116. Hou, Y.; Moreau, F.; Chadee, K. Ppargamma is an e3 ligase that induces the degradation of nfkappab/p65. Nat. Commun. 2012, 3, 1300
117. Hou, Y.; Zhang, Z.; Xu, Q.; Wang, H.; Xu, Y.; Chen, K. Inhibitor of growth 4 induces nfkappab/p65 ubiquitin-dependent degradation. Oncogene 2014, 33, 1997-2003
118. Fan, Y.; Mao, R.; Zhao, Y.; Yu, Y.; Sun, W.; Song, P.; Shi, Z.; Zhang, D.; Yvon, E.; Zhang, H.; et al. Tumor necrosis factor-α induces rela degradation via ubiquitination at lysine 195 to prevent excessive nuclear factor-κb activation. J. Biol. Chem. 2009, 284, 29290-29297
119. Ryo, A.; Suizu, F.; Yoshida, Y.; Perrem, K.; Liou, Y.-C.; Wulf, G.; Rottapel, R.; Yamaoka, S.; Lu, K.P. Regulation of nf-κb signaling by pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/rela. Mol. Cell 2003, 12, 1413-1426
120. Salmeron, A.; Janzen, J.; Soneji, Y.; Bump, N.; Kamens, J.; Allen, H.; Ley, S.C. Direct phosphorylation of nf-kappab1 p105 by the ikappab kinase complex on serine 927 is essential for signal-induced p105 proteolysis. J. Biol. Chem. 2001, 276, 22215-22222
121. Kravtsova-Ivantsiv, Y.; Shomer, I.; Cohen-Kaplan, V.; Snijder, B.; Superti-Furga, G.; Gonen, H.; Sommer, T.; Ziv, T.; Admon, A.; Naroditsky, I.; et al. Kpc1-mediated ubiquitination and proteasomal processing of nf-kappab1 p105 to p50 restricts tumor growth. Cell 2015, 161, 333-347
122. Amir, R.E.; Haecker, H.; Karin, M.; Ciechanover, A. 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 2004, 23, 2540-2547
123. Xiao, G.; Harhaj, E.W.; Sun, S.C. Nf-kappab-inducing kinase regulates the processing of nf-kappab2 p100. Mol. Cell 2001, 7, 401-409
124. Senftleben, U.; Cao, Y.; Xiao, G.; Greten, F.R.; Krahn, G.; Bonizzi, G.; Chen, Y.; Hu, Y.; Fong, A.; Sun, S.C.; et al. Activation by ikkalpha of a second, evolutionary conserved, nf-kappa b signaling pathway. Science 2001, 293, 1495-1499
125. Busino, L.; Millman, S.E.; Scotto, L.; Kyratsous, C.A.; Basrur, V.; O’Connor, O.; Hoffmann, A.; Elenitoba-Johnson, K.S.; Pagano, M. Fbxw7[alpha]- and gsk3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma. Nat. Cell Biol. 2012, 14, 375-385
126. Fukushima, H.; Matsumoto, A.; Inuzuka, H.; Zhai, B.; Lau, A.W.; Wan, L.; Gao, D.; Shaik, S.; Yuan, M.; Gygi, S.P.; et al. Scf(fbw7) modulates the nfkb signaling pathway by targeting nfkb2 for ubiquitination and destruction. Cell Rep. 2012, 1, 434-443
127. Alexander, W.S. Suppressors of cytokine signalling (socs) in the immune system. Nat. Rev. Immunol. 2002, 2, 410-416
128. Maine, G.N.; Mao, X.; Komarck, C.M.; Burstein, E. Commd1 promotes the ubiquitination of nf-κb subunits through a cullin-containing ubiquitin ligase. EMBO J. 2007, 26, 436-447
129. Li, H.; Chan, L.; Bartuzi, P.; Melton, S.D.; Weber, A.; Ben-Shlomo, S.; Varol, C.; Raetz, M.; Mao, X.; Starokadomskyy, P.; et al. Copper metabolism domain-containing 1 represses genes that promote inflammation and protects mice from colitis and colitis-associated cancer. Gastroenterology 2014, 147, 184-195
130. Natoli, G.; Chiocca, S. Nuclear ubiquitin ligases, nf-kappab degradation, and the control of inflammation. Sci. Signal. 2008, 1, pe1
131. Xu, H.; You, M.; Shi, H.; Hou, Y. Ubiquitin-mediated nfkappab degradation pathway. Cell. Mol. Immunol. 2015, 12, 653-655
132. Baetz, A.; Koelsche, C.; Strebovsky, J.; Heeg, K.; Dalpke, A.H. Identification of a nuclear localization signal in suppressor of cytokine signaling 1. FASEB J. 2008, 22, 4296-4305
133. Muller, P.A.; van de Sluis, B.; Groot, A.J.; Verbeek, D.; Vonk, W.I.; Maine, G.N.; Burstein, E.; Wijmenga, C.; Vooijs, M.; Reits, E.; et al. Nuclear-cytosolic transport of commd1 regulates nf-kappab and hif-1 activity. Traffic (Copenhagen, Denmark) 2009, 10, 514-527
134. Strebovsky, J.; Walker, P.; Lang, R.; Dalpke, A.H. Suppressor of cytokine signaling 1 (socs1) limits nfkappab signaling by decreasing p65 stability within the cell nucleus. FASEB J. 2011, 25, 863-874
135. Rodrigues, L.; Filipe, J.; Seldon, M.P.; Fonseca, L.; Anrather, J.; Soares, M.P.; Simas, J.P. Termination of nf-kappab activity through a gammaherpesvirus protein that assembles an ec5s ubiquitin-ligase. EMBO J. 2009, 28, 1283-1295
136. Tanaka, T.; Soriano, M.A.; Grusby, M.J. Slim is a nuclear ubiquitin e3 ligase that negatively regulates stat signaling. Immunity 2005, 22, 729-736
137. Loughran, G.; Healy, N.C.; Kiely, P.A.; Huigsloot, M.; Kedersha, N.L.; O’Connor, R. Mystique is a new insulin-like growth factor-i-regulated pdz-lim domain protein that promotes cell attachment and migration and suppresses anchorage-independent growth. Mol. Biol. Cell 2005, 16, 1811-1822
138. Torrado, M.; Senatorov, V.V.; Trivedi, R.; Fariss, R.N.; Tomarev, S.I. Pdlim2, a novel pdz-lim domain protein, interacts with alpha-actinins and filamin a. Investig. Ophthalmol. Visual Sci. 2004, 45, 3955-3963
139. Healy, N.C.; O’Connor, R. Sequestration of pdlim2 in the cytoplasm of monocytic/macrophage cells is associated with adhesion and increased nuclear activity of nf-kappab. J. Leukoc. Biol. 2009, 85, 481-490
140. Yan, P.; Fu, J.; Qu, Z.; Li, S.; Tanaka, T.; Grusby, M.J.; Xiao, G. Pdlim2 suppresses human t-cell leukemia virus type i tax-mediated tumorigenesis by targeting tax into the nuclear matrix for proteasomal degradation. Blood 2009, 113, 4370-4380
141. Tanaka, T.; Shibazaki, A.; Ono, R.; Kaisho, T. Hsp70 mediates degradation of the p65 subunit of nuclear factor kappab to inhibit inflammatory signaling. Sci. Signal. 2014, 7, ra119
142. Stark, L.A.; Dunlop, M.G. Nucleolar sequestration of rela (p65) regulates nf-κb-driven transcription and apoptosis. Mol. Cell. Biol. 2005, 25, 5985-6004
143. Thoms, H.C.; Loveridge, C.J.; Simpson, J.; Clipson, A.; Reinhardt, K.; Dunlop, M.G.; Stark, L.A. Nucleolar targeting of rela(p65) is regulated by commd1-dependent ubiquitination. Cancer Res. 2010, 70, 139-149
144. Clark, R.B. The role of ppars in inflammation and immunity. J. Leukoc. Biol. 2002, 71, 388-400
145. Chung, S.W.; Kang, B.Y.; Kim, S.H.; Pak, Y.K.; Cho, D.; Trinchieri, G.; Kim, T.S. Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa b. J. Biol. Chem. 2000, 275, 32681-32687
146. Ruan, H.; Pownall, H.J.; Lodish, H.F. Troglitazone antagonizes tumor necrosis factor-α-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of nf-κb. J. Biol. Chem. 2003, 278, 28181-28192
147. Kelly, D.; Campbell, J.I.; King, T.P.; Grant, G.; Jansson, E.A.; Coutts, A.G.P.; Pettersson, S.; Conway, S. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of ppar-[gamma] and rela. Nat. Immunol. 2004, 5, 104-112
148. Garkavtsev, I.; Kozin, S.V.; Chernova, O.; Xu, L.; Winkler, F.; Brown, E.; Barnett, G.H.; Jain, R.K. The candidate tumour suppressor protein ing4 regulates brain tumour growth and angiogenesis. Nature 2004, 428, 328-332
149. Coles, A.H.; Gannon, H.; Cerny, A.; Kurt-Jones, E.; Jones, S.N. Inhibitor of growth-4 promotes ikappab promoter activation to suppress nf-kappab signaling and innate immunity. Proc. Natl. Acad. Sci. USA 2010, 107, 11423-11428
150. Everett, R.D. Icp0, a regulator of herpes simplex virus during lytic and latent infection. BioEssays News Rev. Mol. Cell. Dev. Biol. 2000, 22, 761-770
151. Zhang, J.; Wang, K.; Wang, S.; Zheng, C. Herpes simplex virus 1 e3 ubiquitin ligase icp0 protein inhibits tumor necrosis factor alpha-induced nf-kappab activation by interacting with p65/rela and p50/nf-kappab1. J. Virol. 2013, 87, 12935-12948
152. Boutell, C.; Sadis, S.; Everett, R.D. Herpes simplex virus type 1 immediate-early protein icp0 and its isolated ring finger domain act as ubiquitin e3 ligases in vitro. J. Virol. 2002, 76, 841-850
153. Chang, M.; Jin, W.; Chang, J.H.; Xiao, Y.; Brittain, G.C.; Yu, J.; Zhou, X.; Wang, Y.H.; Cheng, X.; Li, P.; et al. The ubiquitin ligase peli1 negatively regulates t cell activation and prevents autoimmunity. Nat. Immunol. 2011, 12, 1002-1009
154. Chen, E.; Hrdlickova, R.; Nehyba, J.; Longo, D.L.; Bose, H.R., Jr.; Li, C.C. Degradation of proto-oncoprotein c-rel by the ubiquitin-proteasome pathway. J. Biol. Chem. 1998, 273, 35201-35207
155. Zarnegar, B.J.; Wang, Y.; Mahoney, D.J.; Dempsey, P.W.; Cheung, H.H.; He, J.; Shiba, T.; Yang, X.; Yeh, W.-C.; Mak, T.W.; et al. Noncanonical nf-[kappa]b 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
156. Vallabhapurapu, S.; Matsuzawa, A.; Zhang, W.; Tseng, P.H.; Keats, J.J.; Wang, H.; Vignali, D.A.; Bergsagel, P.L.; Karin, M. 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
157. Jin, J.; Xiao, Y.; Hu, H.; Zou, Q.; Li, Y.; Gao, Y.; Ge, W.; Cheng, X.; Sun, S.-C. Proinflammatory tlr signalling is regulated by a traf2-dependent proteolysis mechanism in macrophages. Nat. Commun. 2015, 6
158. Xia, Z.P.; Chen, Z.J. Traf2: A double-edged sword? Sci. STKE 2005, 2005, pe7
159. Hacker, H.; Tseng, P.H.; Karin, M. Expanding traf function: Traf3 as a tri-faced immune regulator. Nat. Rev. Immunol. 2011, 11, 457-468
160. Hochrainer, K.; Pejanovic, N.; Olaseun, V.A.; Zhang, S.; Iadecola, C.; Anrather, J. The ubiquitin ligase herc3 attenuates nf-κb-dependent transcription independently of its enzymatic activity by delivering the rela subunit for degradation. Nucleic Acids Res. 2015, 43, 9889-9904
161. Nicholson, B.; Suresh Kumar, K.G. The multifaceted roles of usp7: New therapeutic opportunities. Cell Biochem. Biophys. 2011, 60, 61-68
162. Holowaty, M.N.; Sheng, Y.; Nguyen, T.; Arrowsmith, C.; Frappier, L. Protein interaction domains of the ubiquitin-specific protease, usp7/hausp. J. Biol. Chem. 2003, 278, 47753-47761
163. Faesen, A.C.; Dirac, A.M.; Shanmugham, A.; Ovaa, H.; Perrakis, A.; Sixma, T.K. Mechanism of usp7/hausp activation by its c-terminal ubiquitin-like domain and allosteric regulation by gmp-synthetase. Mol. Cell 2011, 44, 147-159
164. Zapata, J.M.; Pawlowski, K.; Haas, E.; Ware, C.F.; Godzik, A.; Reed, J.C. A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains. J. Biol. Chem. 2001, 276, 24242-24252
165. Schaefer, J.B.; Morgan, D.O. Protein-linked ubiquitin chain structure restricts activity of deubiquitinating enzymes. J. Biol. Chem. 2011, 286, 45186-45196
166. Cheon, K.W.; Baek, K.H. Hausp as a therapeutic target for hematopoietic tumors (review). Int. J. Oncol. 2016, 28, 1209-1215
167. Zhang, Y.; Zhou, L.; Rouge, L.; Phillips, A.H.; Lam, C.; Liu, P.; Sandoval, W.; Helgason, E.; Murray, J.M.; Wertz, I.E.; Corn, J.E. Conformational stabilization of ubiquitin yields potent and selective inhibitors of usp7. Nat. Chem. Biol. 2013, 9, 51-58
168. Wrigley, J.D.; Eckersley, K.; Hardern, I.M.; Millard, L.; Walters, M.; Peters, S.W.; Mott, R.; Nowak, T.; Ward, R.A.; Simpson, P.B.; et al. Enzymatic characterisation of usp7 deubiquitinating activity and inhibition. Cell Biochem. Biophys. 2011, 60, 99-111
169. Kashiwaba, S.; Kanao, R.; Masuda, Y.; Kusumoto-Matsuo, R.; Hanaoka, F.; Masutani, C. Usp7 is a suppressor of pcna ubiquitination and oxidative-stress-induced mutagenesis in human cells. Cell Rep. 2015, 13, 2072-2080
170. Zlatanou, A.; Sabbioneda, S.; Miller, E.S.; Greenwalt, A.; Aggathanggelou, A.; Maurice, M.M.; Lehmann, A.R.; Stankovic, T.; Reverdy, C.; Colland, F.; et al. Usp7 is essential for maintaining rad18 stability and DNA damage tolerance. Oncogene 2016, 35, 965-976
171. Glickman, M.H.; Ciechanover, A. The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction. Physiol. Rev. 2002, 82, 373-428
172. Rape, M.; Jentsch, S. Taking a bite: Proteasomal protein processing. Nat. Cell Biol. 2002, 4, E113-E116
173. Fan, C.M.; Maniatis, T. Generation of p50 subunit of nf-kappa b by processing of p105 through an atp-dependent pathway. Nature 1991, 354, 395-398
174. Palombella, V.J.; Rando, O.J.; Goldberg, A.L.; Maniatis, T. The ubiquitin-proteasome pathway is required for processing the nf-kappa b1 precursor protein and the activation of nf-kappa b. Cell 1994, 78, 773-785
175. Betts, J.C.; Nabel, G.J. Differential regulation of nf-kappab2(p100) processing and control by amino-terminal sequences. Mol. Cell Biol. 1996, 16, 6363-6371
176. Heusch, M.; Lin, L.; Geleziunas, R.; Greene, W.C. The generation of nfkb2 p52: Mechanism and efficiency. Oncogene 1999, 18, 6201-6208
177. Orian, A.; Whiteside, S.; Israël, A.; Stancovski, I.; Schwartz, A.L.; Ciechanover, A. Ubiquitin-mediated processing of nf-κb transcriptional activator precursor p105: Reconstitution of a cell-free system and identification of the ubiquitin-carrier protein, e2, and a novel ubiquitin-protein ligase, e3, involved in conjugation. J. Biol. Chem. 1995, 270, 21707-21714
178. Lin, L.; DeMartino, G.N.; Greene, W.C. Cotranslational biogenesis of nf-κb p50 by the 26s proteasome. Cell 1998, 92, 819-828
179. Lin, L.; DeMartino, G.N.; Greene, W.C. Cotranslational dimerization of the Rel homology domain of NF-κB1 generates p50-p105 heterodimers and is required for effective p50 production. EMBO J. 2000, 19, 4712-4722
180. Rice, N.R.; MacKichan, M.L.; Israel, A. The precursor of nf-kappa b p50 has i kappa b-like functions. Cell 1992, 71, 243-253
181. Mercurio, F.; DiDonato, J.A.; Rosette, C.; Karin, M. P105 and p98 precursor proteins play an active role in nf-kappa b-mediated signal transduction. Genes Dev. 1993, 7, 705-718
182. Basak, S.; Kim, H.; Kearns, J.D.; Tergaonkar, V.; O’Dea, E.; Werner, S.L.; Benedict, C.A.; Ware, C.F.; Ghosh, G.; Verma, I.M.; et al. A fourth iκb protein within the nf-κb signaling module. Cell 2007, 128, 369-381
183. Liou, H.C.; Nolan, G.P.; Ghosh, S.; Fujita, T.; Baltimore, D. The nf-kappa b p50 precursor, p105, contains an internal i kappa b-like inhibitor that preferentially inhibits p50. EMBO J. 1992, 11, 3003-3009
184. Savinova, O.V.; Hoffmann, A.; Ghosh, G. The nfkb1 and nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. Mol. Cell 2009, 34, 591-602
185. Coux, O.; Goldberg, A.L. Enzymes catalyzing ubiquitination and proteolytic processing of the p105 precursor of nuclear factor κb1. J. Biol. Chem. 1998, 273, 8820-8828
186. Fujimoto, K.; Yasuda, H.; Sato, Y.; Yamamoto, K. A role for phosphorylation in the proteolytic processing of the human nf-kappa b1 precursor. Gene 1995, 165, 183-189
187. MacKichan, M.L.; Logeat, F.; Israel, A. Phosphorylation of p105 pest sequence via a redox-insensitive pathway up-regulates processing of p50 nf-kappab. J. Biol. Chem. 1996, 271, 6084-6091
188. Orian, A.; Gonen, H.; Bercovich, B.; Fajerman, I.; Eytan, E.; Israel, A.; Mercurio, F.; Iwai, K.; Schwartz, A.L.; Ciechanover, A. Scf[beta]-trcp ubiquitin ligase-mediated processing of nf-[kappa]b p 105 requires phosphorylation of its c-terminus by i[kappa]b kinase. EMBO J. 2000, 19, 2580-2591
189. Heissmeyer, V.; Krappmann, D.; Hatada, E.N.; Scheidereit, C. Shared pathways of iκb kinase-induced scfβtrcp-mediated ubiquitination and degradation for the nf-κb precursor p105 and iκbα. Mol. Cell. Biol. 2001, 21, 1024-1035
190. Lang, V.; Janzen, J.; Fischer, G.Z.; Soneji, Y.; Beinke, S.; Salmeron, A.; Allen, H.; Hay, R.T.; Ben-Neriah, Y.; Ley, S.C. Btrcp-mediated proteolysis of nf-κb1 p105 requires phosphorylation of p105 serines 927 and 932. Mol. Cell. Biol. 2003, 23, 402-413
191. Cohen, S.; Achbert-Weiner, H.; Ciechanover, A. Dual effects of iκb kinase β-mediated phosphorylation on p105 fate: Scfβ-trcp-dependent degradation and scfβ-trcp-independent processing. Mol. Cell. Biol. 2004, 24, 475-486
192. Cohen, S.; Lahav-Baratz, S.; Ciechanover, A. Two distinct ubiquitin-dependent mechanisms are involved in nf-kappab p105 proteolysis. Biochem. Biophys. Res. Commun. 2006, 345, 7-13
193. Lin, L.; Ghosh, S. A glycine-rich region in nf-kappab p105 functions as a processing signal for the generation of the p50 subunit. Molecular and Cellular Biology 1996, 16, 2248-2254
194. Orian, A.; Schwartz, A.L.; Israël, A.; Whiteside, S.; Kahana, C.; Ciechanover, A. Structural motifs involved in ubiquitin-mediated processing of the nf-κb precursor p105: Roles of the glycine-rich region and a downstream ubiquitination domain. Mol. Cell. Biol. 1999, 19, 3664-3673
195. Ciechanover, A.; Gonen, H.; Bercovich, B.; Cohen, S.; Fajerman, I.; Israel, A.; Mercurio, F.; Kahana, C.; Schwartz, A.L.; Iwai, K.; et al. Mechanisms of ubiquitin-mediated, limited processing of the nf-kappab1 precursor protein p105. Biochimie 2001, 83, 341-349
196. Moorthy, A.K.; Savinova, O.V.; Ho, J.Q.; Wang, V.Y.-F.; Vu, D.; Ghosh, G. The 20s proteasome processes nf-κb1 p105 into p50 in a translation-independent manner. EMBO J. 2006, 25, 1945-1956
197. Sun, S.C. Non-canonical nf-kappab signaling pathway. Cell Res. 2011, 21, 71-85
198. Sun, S.C. The noncanonical nf-kappab pathway. Immunol. Rev. 2012, 246, 125-140
199. Coope, H.J.; Atkinson, P.G.; Huhse, B.; Belich, M.; Janzen, J.; Holman, M.J.; Klaus, G.G.; Johnston, L.H.; Ley, S.C. Cd40 regulates the processing of nf-kappab2 p100 to p52. EMBO J. 2002, 21, 5375-5385
200. Liang, C.; Zhang, M.; Sun, S.C. Beta-trcp binding and processing of nf-kappab2/p100 involve its phosphorylation at serines 866 and 870. Cell. Signal. 2006, 18, 1309-1317
201. Fong, A.; Sun, S.C. Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of nf-kappa b2/p100. J. Biol. Chem. 2002, 277, 22111-22114
202. Fong, A.; Zhang, M.; Neely, J.; Sun, S.C. S9, a 19 s proteasome subunit interacting with ubiquitinated nf-kappab2/p100. J. Biol. Chem. 2002, 277, 40697-40702
203. Cohen, P.; Tcherpakov, M. Will the ubiquitin system furnish as many drug targets as protein kinases? Cell 2010, 143, 686-693
204. Gilmore, T.D.; Herscovitch, M. Inhibitors of NF-κB signaling: 785 and counting. Oncogene 2006, 25, 6887-6899