Melis ŞEN, Ulaş AY, Ece AKBAYIR, Seray ŞENYER, Erdem TÜZÜN, Cem İsmail KÜÇÜKALİ

NF-κB, SUMO ve Ubikitinasyon İlişkisi

NF-κB, DNA’ya doğrudan bağlanarak genlerin ekspresyonunu düzenleyen bir transkripsiyon faktörüdür.İmmünitede, hücre sağkalımında, hücre çoğalmasında, öğrenme ve bellek süreçlerinde görevlidir.Post-translasyonel modifikasyonda görevli olan SUMO proteini eksprese edilen proteinlerin fonksiyonlarınıdüzenler ve memelilerde dört adet homoloğu bulunmaktadır.Bir diğer posttranslasyonel modifikasyonda görevli olan protein ise ubikitindir. Birçok biyolojik yolaktayer alır ve işaretlediği proteinleri proteozom sistemine yönlendirerek yıkımını sağlar.Bu derlemede NF-κB, SUMO ve ubikitin proteinlerinden ve birbirleriyle olan ilişkilerinden bahsedilecektir.

Anahtar Kelimeler:

NF-κB, SUMO, Sumoylasyon, Ubikitin, Ubikitinasyon, Ubikitin-proteozom sistemi

NF-κB, SUMO and Ubiquitination Relationship

NF-κB is a transcription factor that regulates the expression of genes by directly binding to DNA.It’s involved in immune system, cell survival, cell proliferation, learning and memory processes.The SUMO protein, which is involved in post-translational modification, regulates the function ofexogenous proteins and there are four homologs in mammals.Another protein involved in post-translational modification is ubiquitin. It is involved in many biologicalpathways and leads the marked proteins to destruction by directing them to the proteosomesystem.In this review NF-κB, SUSMO and ubiquitin proteins and their relationship to each other will bediscussed.

Keywords:

NF-κB, SUMO, Sumolation, Ubiquitin, Ubiquitination, Ubiquitin-Proteosome system,

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1. Schmitz ML, Mattioli I, Buss H, Kracht M. NF- κB: A multifaceted transcription factor regulated at several levels. Chem Bio Chem 2004; 5: 1348-1358. 2. Sen R, Baltimore D. Multiple nuclear factors interact with the immunglobulin enhancer sequences. Cell 1988; 46: 705- 716. 3. Zhang L, Badgwell DB, Bevers JJ, Schlessinger K, Murray PJ, Levy DE, Watowich SS. IL-6 signaling via the STAT3/SOCS3 pathways: Functional analysis of the conserved STAT3 N-domain. Mol Cell Biochem 2006; 288 (1- 2): 179-189. 4. Sun XF, Zhang H. NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases. Histol Histopathol 2007; 22: 1387-1398. 5. Dalmızrak A, Kosova B. TANK proteininin sinyal iletimindeki fonksiyonel analizi. Yüksek Lisans Tezi, İzmir 2005. 6. Ekinci Ö, Memis L. Küçük hücreli dışı akciğer karsinomlarında nükleer faktör kappa B immünohistokimyasal ekspresyonunun prognozla ilişkisi. Gazi Tıp Dergisi 2008; 19 (1): 1-5. 7. Camandola S, Mattson MP. NF-κB as a therapeutic target in neurodegenerative diseases. Expert Opin Ther Targets 2007; 11 (2): 123-131. 8. Calzado MA, Bacher S, Schmitz ML. NF- ĸB inhibitors for the treatment of inflammatory diseases and cancer. Curr Med Chem 2007; 14: 367-376. 9. Hoffman A, Baltimore D. Circuitry of nuclear factor κB signalling. Immunol Rev 2006; 210: 171-186. 10. Ling L, Cao Z, Goeddel DV. NF-kappaB-inducing kinase activates IKKalpha by phosphorylation of Ser-176. Proc Natl Acad Sci USA 1998; 95: 3792-3797. 11. Lindström TM, Bennett PR. The role of nuclear factor kappa B in human labour. Reprodu-ction 2005; 130: 569-581. 12. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF- κB pathway in the treatment of inflammation and cancer. The J Clin Invest 2001; 107 (2): 135-142. 13. Umezawa K. Inhibition of tumor growth by NF-κB inhibitors. Cancer Sci 2006; 97 (10): 990- 995 14. Melchior F, Schergaut M, Pichler A. SUMO: ligases, isopeptidases and nuclear pores. Trends in Biochemic Sci 2003; 28: 612-618. 15. Melchior F. SUMO – nonlassical ubiquitin. Annu Rev Cell Dev Biol 2000; 16: 591-626. 16. Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem 1998; 273 (18): 11349-11353. 17. Saitoh H, Hinchey J. Functional Heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem 2000; 275: 6252-6258. 18. Kolli N, Mikolajczyk J, Drag M, Mukhopadhyay D, Moffatt N, Dasso M, Salvesen G, Wilkinson KD. Distribution and parlogue specificity of mammalian deSUMOylating enzymes. Biochem J 2010; 430: 335-344. 19. Ayaydin F, Dasso M. Distinct in vivo dynamics of vertebrate SUMO paralogues. Mol Biol Cell 2004; 15: 5208-5218. 20. Tatham MH, Jaffray E, Vaughan OA, Desterro JMP, Botting CH, Naismith JH, Hay RT. Polymeric Chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/ SAE2 and Ubc9. J Bio Chem 2001; 276 (38): 35368-35374. 21. Matic I, van Hagen M, Schimmel J, Macek B, Ogg SC, Tatham MH, Hay RT, Lamond AI, Mann M, Vertegaal ACO. In vivo identification of human small ubiquitin-like modifier polymerization sites by high accuracy mass spectometry and an in vitro to in vivo strategy. Moll Cell Preotomics 2008; 7: 132-144. 22. Rodriguez MS, Desterro JM, Lain S, Midgley CA, Lane DP, Hay RT. SUMO-1 modification activates the transcriptional response of p53. EMBO J 1999; 15: 6455-6461. 23. Bohren KM, Nadkarni V, Song JH, Gabby KH, Owerbach D. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat schock transcirption factors and is associated with susceptibility to type I diabetes mellitus. J Biol Chem 2004; 279: 27233-27238. 24. Martin S, Wilkinson KA, Nishimune A, Henly JM. Emerging exracellular roles of protein SUMOylation in neuronal function and dysfunction. Nat Rev Neurosci 2007; 8 (12): 948-959. 25. Song J, Durrin LK, Wilkinson TA, Krontiris TG, Chen Y. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc Natl Acad Sci 2004; 101: 14373- 14378. 26. Hayashi T, Seki M, Maeda D, Wang W, Kawabe Y, Seki T, Saitoh H, Fukugawa T, Yagi H, Enomoto T. Ubc9 is essential for viability of higher eukaryotic cells. Exp Cell Res 2002; 280 (2): 212-221. 27. Wilkinson KA, Nakamura Y, Henley JM. Targets and consequences of protein SUMOylation in neurons. Brain Res Rev 2010; 64 (1); 195-212. 28. Wilkinson KA, Henley JM. Mechanisms, regulation and consequences of protein SUMOylation Biochem J 2012; 428 (2): 133-145. 29. Gong L, Li B, Millas S, Yeh ET. Molecular cloning and characterization of human AOS1 and UBA2, cmponents of the sentrin-activating enzyme complex. FEBS Lett 1999; 448: 185-189. 30. Johnson ES, Blobel G. Ubc9p is the conjugating enzyme for the ubiquitin-like protein Smtp3. J Biol Chem 1997; 272: 26799-26802. 31. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67, 425-479. 32. Varshavsky A. The early history of the ubiquitin field. Protein Sci 2006; 15 (3): 647-654. 33. Clague MJ, Heride C, Urbe S. The demographics of the ubiquitin system. Trends Cell Biol 2015; 25: 417-426. 34. Komander D, Rape M. The ubiquitin code. Annu Rev Biochem 2012; 81: 203-229. 35. Ikeda F, Dikic I. Atypical ubiquitin chains: new molecular signals. Protein modifications: beyond the usual suspects’ review series. EMBO Rep 2008; 9: 536 – 542 36. Swatek KN, Komander D. Ubiquitin modifications, Cell Res 2016; 26: 399–422. 37. Husnjak K, Dikic I. Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem 2012; 81: 291-322. 38. Hurley JH, Lee S, Prag G. Ubiquitin-binding domains. Biochem J 2006; 399:361-372. 39. Sun Y. Targeting E3 ubiquitin ligases for cancer therapy. Cancer Biol Ther 2003; 2 (6): 623-629. 40. Finley D. Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem 2009; 78: 477-513. 41. Smith DM, Chang SC, Park S, Finley D, Cheng Y, Goldberg AL. Docking of the proteasomal ATPases’ carboxyl termini in the 20S proteasome’s alpha ring opens the gate for subst-rate entry. Mol Cell 2007; 27 (5): 731-744. 42. Ciechanovera A, Schwartzb AL. The ubiquitin system: pathogenesis of human diseases and drug targeting. Biochimica et Biophysica Acta (BBA) 2004; 1695: 3-17. 43. Chen J, Chen JZ. Regulation of NF-κB by Ubiquitination. Curr Opin Immunol 2013; 25 (1): 4-12. 44. Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-kappaB regulatory pathways. Annu Rev Biochem 2009; 78: 769-796. 45. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NFkB activity. Annu Rev Immunol 2000; 18: 621-663. 46. Etzioni A, Ciechanover A, Pikarsky E. Immune defects caused by mutations in the ubiquitin system. J Allergy Clin Immunol 2017; 139: 743-753. 47. Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation. Nat Cell Biol 2006; 8: 398-406. 48. 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. 49. Terzic J, Dikic I. Interplay between ubiquitin networks and NF-κB signaling. Period Biol 2011; 113 (1): 1-6. 50. Desterro JM, Rodriguez MS, Hay RT. SUMO- 1 modification of IkappaBalpha inhibits NF-kappa-B activation. Mol Cell 1998; 2: 233-239. 51. Hayden MS, Ghosh S. Signalling to NF-kappaB. Genes Dev 2004; 18: 2195-2224. 52. Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T. Signal-induced site-specific phosphorylation target I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev 1995; 9: 1586-1697. 53. Magnani M, Crinelli R, Bianchi M, Antonelli A. The ubiquitin-dependent proteolytic system and other potential targets for the modulation of nuclear factor-ĸb (NF-ĸb). Curr Drug Targets 2000; 1: 387-399. 54. Wilson WG. SUMO regulation of cellular processes, advances in experimental medicine and biology. Springer, Berlin, Germany, 2nd ed. 2017; pp 1-12. 55. Chen A, Mannen H, Li SS. Characterization of mouse ubiquitin-like SMT3A and SMT3B cDNAs and gene/pseudogenes. Biochem Mol Biol Int 1998; 46: 1161-1174. 56. Bayer P, Arndt A, Metzger S, Mahajan R, Melchior F, Jaenicke R, Becker J. Structure determination of the small ubiquitin-related modifier SUMO-1. J Mol Biol 1998; 280: 275-286. 57. Lois LM, Lima CD. Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1. EMBO J 2005; 24: 439-451. 58. Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem 2009; 78: 399-434. 59. Gareau JR, Lima CD. The SUMO pathway: Emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 2010; 11: 861-871. 60. Escobar-Ramirez A, Vercoutter-Edouart AS, Mortuaire M, Huvent I, Hardivillé S, Hoedt E, Lefebvre T, Pierce A. Modification by SUMOylation Controls Both the Transcriptional Activity and the Stability of Delta-Lactoferrin. PloS one, DOI:10.1371/journal. pone.0129965, Jun 15, 2015. 61. Klenk C, Humrich J, Quitterer U, Lohse MJ. SUMO-1 controls the protein stability and the biological function of phosducin. J Biol Chem 2006; 281: 8357-8364. 62. Jackson SP, Durocher D. Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell 2013; 49: 795-807. 63. Nie M, Aslanian A, Prudden J, Heideker J, Vashisht AA, Wohlschlegel JA, Yates JR, Boddy MN. Dual recruitment of Cdc48 (p97)- Ufd1-Npl4 ubiquitin-selective segregase by small ubiquitin-like modifier protein (SUMO) and ubiquitin in SUMO-targeted ubiquitin ligase- mediated genome stability functions. J Biol Chem 2012; 287 (35): 29610-29619. 64. Ulrich HD. Ubiquitin and SUMO in DNA repair at a glance. J Cell Sci 2012; 125: 249-254