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Cited by 127Genomics and Chromatin DynamicsT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

CIITA and Its Dual Roles in MHC Gene Transcription

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Devaiah, Ballachanda N., Singer, Dinah S.·2013·Frontiers in Immunology
DOI 10.3389/fimmu.2013.00476PMC PMC3868913
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Abstract

Class II transactivator (CIITA) is a transcriptional coactivator that regulates γ-interferon-activated transcription of Major Histocompatibility Complex (MHC) class I and II genes. As such, it plays a critical role in immune responses: CIITA deficiency results in aberrant MHC gene expression and consequently in autoimmune diseases such as Type II bare lymphocyte syndrome. Although CIITA does not bind DNA directly, it regulates MHC transcription in two distinct ways - as a transcriptional activator and as a general transcription factor. As an activator, CIITA nucleates an enhanceosome consisting of the DNA binding transcription factors RFX, cyclic AMP response element binding protein, and NF-Y. As a general transcription factor, CIITA functionally replaces the TFIID component, TAF1. Like TAF1, CIITA possesses acetyltransferase (AT) and kinase activities, both of which contribute to proper transcription of MHC class I and II genes. The substrate specificity and regulation of the CIITA AT and kinase activities also parallel those of TAF1. In addition, CIITA is tightly regulated by its various regulatory domains that undergo phosphorylation and influence its targeted localization. Thus, a complex picture of the mechanisms regulating CIITA function is emerging suggesting that CIITA has dual roles in transcriptional regulation which are summarized in this review.

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Research works printed but not linked: 49

  1. [1]Steimle V Otten LA Zufferey M Mach B Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell (1993) 75(1): 135– 46 10.1016/0092-8674(93)90685-J 8402893 · DOI
  2. [2]Vora AR Rodgers S Parker AJ Start R Rees RC Murray AK An immunohistochemical study of altered immunomodulatory molecule expression in head and neck squamous cell carcinoma. Br J Cancer (1997) 76(7): 836– 44 10.1038/bjc.1997.472 9328140 PMC2228257 · DOI
  3. [3]Nagarajan UM Bushey A Boss JM Modulation of gene expression by the MHC class II transactivator. J Immunol (2002) 169(9): 5078– 88 12391224
  4. [4]Mori-Aoki A Pietrarelli M Nakazato M Caturegli P Kohn LD Suzuki K Class II transactivator suppresses transcription of thyroid-specific genes. Biochem Biophys Res Commun (2000) 278(1): 58– 62 10.1006/bbrc.2000.3769 11071855 · DOI
  5. [5]Masternak K Muhlethaler-Mottet A Villard J Zufferey M Steimle V Reith W CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with an enhanceosome complex. Genes Dev (2000) 14(9): 1156– 66 10.1101/gad.14.9.1156 10809673 PMC316580 · DOI
  6. [6]Fontes JD Kanazawa S Nekrep N Peterlin BM The class II transactivator CIITA is a transcriptional integrator. Microbes Infect (1999) 1(11): 863– 9 10.1016/S1286-4579(99)00232-4 10614003 · DOI
  7. [7]Raval A Howcroft TK Weissman JD Kirshner S Zhu XS Yokoyama K Transcriptional coactivator, CIITA, is an acetyltransferase that bypasses a promoter requirement for TAF(II)250. Mol Cell (2001) 7(1): 105– 15 10.1016/S1097-2765(01)00159-9 11172716 · DOI
  8. [8]Devaiah BN Lu H Gegonne A Sercan Z Zhang H Clifford RJ Novel functions for TAF7, a regulator of TAF1-independent transcription. J Biol Chem (2010) 285(50): 38772– 80 10.1074/jbc.M110.173864 20937824 PMC2998114 · DOI
  9. [9]Soe KC Devaiah BN Singer DS Transcriptional coactivator CIITA, a functional homolog of TAF1, has kinase activity. Biochim Biophys Acta (2013) 1829(11): 1184– 90 10.1016/j.bbagrm.2013.09.001 24036077 PMC3816002 · DOI
  10. [10]Harton JA Linhoff MW Zhang J Ting JP Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol (2002) 169(8): 4088– 93 12370334
  11. [11]Lich JD Ting JP CATERPILLER (NLR) family members as positive and negative regulators of inflammatory responses. Proc Am Thorac Soc (2007) 4(3): 263– 6 10.1513/pats.200701-022AW 17607010 PMC2647628 · DOI
  12. [12]Chin KC Mao C Skinner C Riley JL Wright KL Moreno CS Molecular analysis of G1B and G3A IFN gamma mutants reveals that defects in CIITA or RFX result in defective class II MHC and Ii gene induction. Immunity (1994) 1(8): 687– 97 10.1016/1074-7613(94)90039-6 7600294 · DOI
  13. [14]Wu X Kong X Luchsinger L Smith BD Xu Y Regulating the activity of class II transactivator by posttranslational modifications: exploring the possibilities. Mol Cell Biol (2009) 29(21): 5639– 44 10.1128/MCB.00661-09 19720744 PMC2772741 · DOI
  14. [15]Linhoff MW Harton JA Cressman DE Martin BK Ting JP Two distinct domains within CIITA mediate self-association: involvement of the GTP-binding and leucine-rich repeat domains. Mol Cell Biol (2001) 21(9): 3001– 11 10.1128/MCB.21.9.3001-3011.2001 11287606 PMC86929 · DOI
  15. [16]Tosi G Jabrane-Ferrat N Peterlin BM Phosphorylation of CIITA directs its oligomerization, accumulation and increased activity on MHCII promoters. EMBO J (2002) 21(20): 5467– 76 10.1093/emboj/cdf557 12374747 PMC129089 · DOI
  16. [17]Harton JA Cressman DE Chin KC Der CJ Ting JP GTP binding by class II transactivator: role in nuclear import. Science (1999) 285(5432): 1402– 5 10.1126/science.285.5432.1402 10464099 · DOI
  17. [18]Raval A Weissman JD Howcroft TK Singer DS The GTP-binding domain of class II transactivator regulates its nuclear export. J Immunol (2003) 170(2): 922– 30 12517958
  18. [19]Fontes JD Jiang B Peterlin BM The class II trans-activator CIITA interacts with the TBP-associated factor TAFII32. Nucleic Acids Res (1997) 25(12): 2522– 8 10.1093/nar/25.12.2522 9171108 PMC146770 · DOI
  19. [20]Sisk TJ Gourley T Roys S Chang CH MHC class II transactivator inhibits IL-4 gene transcription by competing with NF-AT to bind the coactivator CREB binding protein (CBP)/p300. J Immunol (2000) 165(5): 2511– 7 10946277
  20. [21]Chin KC Li GG Ting JP Importance of acidic, proline/serine/threonine-rich, and GTP-binding regions in the major histocompatibility complex class II transactivator: generation of transdominant-negative mutants. Proc Natl Acad Sci U S A (1997) 94(6): 2501– 6 10.1073/pnas.94.6.2501 9122224 PMC20117 · DOI
  21. [22]Hake SB Masternak K Kammerbauer C Janzen C Reith W Steimle V CIITA leucine-rich repeats control nuclear localization, in vivo recruitment to the major histocompatibility complex (MHC) class II enhanceosome, and MHC class II gene transactivation. Mol Cell Biol (2000) 20(20): 7716– 25 10.1128/MCB.20.20.7716-7725.2000 11003667 PMC86349 · DOI
  22. [23]Harton JA Ting JP Class II transactivator: mastering the art of major histocompatibility complex expression. Mol Cell Biol (2000) 20(17): 6185– 94 10.1128/MCB.20.17.6185-6194.2000 10938095 PMC86093 · DOI
  23. [24]Sisk TJ Roys S Chang CH Self-association of CIITA and its transactivation potential. Mol Cell Biol (2001) 21(15): 4919– 28 10.1128/MCB.21.15.4919-4928.2001 11438649 PMC87215 · DOI
  24. [25]Schnappauf F Hake SB Camacho Carvajal MM Bontron S Lisowska-Grospierre B Steimle V N-terminal destruction signals lead to rapid degradation of the major histocompatibility complex class II transactivator CIITA. Eur J Immunol (2003) 33(8): 2337– 47 10.1002/eji.200323490 12884309 · DOI
  25. [26]Muhlethaler-Mottet A Otten LA Steimle V Mach B Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA. EMBO J (1997) 16(10): 2851– 60 10.1093/emboj/16.10.2851 9184229 PMC1169893 · DOI
  26. [27]Ni Z Abou El Hassan M Xu Z Yu T Bremner R The chromatin-remodeling enzyme BRG1 coordinates CIITA induction through many interdependent distal enhancers. Nat Immunol (2008) 9(7): 785– 93 10.1038/ni.1619 18500344 · DOI
  27. [28]Ting JP Trowsdale J Genetic control of MHC class II expression. Cell (2002) 109(Suppl): S21– 33 10.1016/S0092-8674(02)00696-7 11983150 · DOI
  28. [29]Choi NM Majumder P Boss JM Regulation of major histocompatibility complex class II genes. Curr Opin Immunol (2011) 23(1): 81– 7 10.1016/j.coi.2010.09.007 20970972 PMC3033992 · DOI
  29. [30]Zhu XS Linhoff MW Li G Chin KC Maity SN Ting JP Transcriptional scaffold: CIITA interacts with NF-Y, RFX, and CREB to cause stereospecific regulation of the class II major histocompatibility complex promoter. Mol Cell Biol (2000) 20(16): 6051– 61 10.1128/MCB.20.16.6051-6061.2000 10913187 PMC86081 · DOI
  30. [31]Wright KL Ting JP Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol (2006) 27(9): 405– 12 10.1016/j.it.2006.07.007 16870508 · DOI
  31. [32]Zika E Ting JP Epigenetic control of MHC-II: interplay between CIITA and histone-modifying enzymes. Curr Opin Immunol (2005) 17(1): 58– 64 10.1016/j.coi.2004.11.008 15653312 · DOI
  32. [33]Mudhasani R Fontes JD Multiple interactions between BRG1 and MHC class II promoter binding proteins. Mol Immunol (2005) 42(6): 673– 82 10.1016/j.molimm.2004.09.021 15781111 · DOI
  33. [34]Roeder RG The role of general initiation factors in transcription by RNA polymerase II. Trends Biochem Sci (1996) 21(9): 327– 35 10.1016/0968-0004(96)10050-5 8870495 · DOI
  34. [35]Mizzen CA Yang XJ Kokubo T Brownell JE Bannister AJ Owen-Hughes T The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell (1996) 87(7): 1261– 70 10.1016/S0092-8674(00)81821-8 8980232 · DOI
  35. [36]Dikstein R Ruppert S Tjian R TAFII250 is a bipartite protein kinase that phosphorylates the base transcription factor RAP74. Cell (1996) 84(5): 781– 90 10.1016/S0092-8674(00)81055-7 8625415 · DOI
  36. [37]Weissman JD Howcroft TK Singer DS TAF(II)250-independent transcription can be conferred on a TAF(II)250-dependent basal promoter by upstream activators. J Biol Chem (2000) 275(14): 10160– 7 10.1074/jbc.275.14.10160 10744699 · DOI
  37. [38]Howcroft TK Raval A Weissman JD Gegonne A Singer DS Distinct transcriptional pathways regulate basal and activated major histocompatibility complex class I expression. Mol Cell Biol (2003) 23(10): 3377– 91 10.1128/MCB.23.10.3377-3391.2003 12724398 PMC154244 · DOI
  38. [39]Mahanta SK Scholl T Yang FC Strominger JL Transactivation by CIITA, the type II bare lymphocyte syndrome-associated factor, requires participation of multiple regions of the TATA box binding protein. Proc Natl Acad Sci U S A (1997) 94(12): 6324– 9 10.1073/pnas.94.12.6324 9177216 PMC21048 · DOI
  39. [40]Kanazawa S Okamoto T Peterlin BM Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity (2000) 12(1): 61– 70 10.1016/S1074-7613(00)80159-4 10661406 · DOI
  40. [41]Gegonne A Weissman JD Singer DS TAFII55 binding to TAFII250 inhibits its acetyltransferase activity. Proc Natl Acad Sci U S A (2001) 98(22): 12432– 7 10.1073/pnas.211444798 11592977 PMC60071 · DOI
  41. [42]Gegonne A Weissman JD Zhou M Brady JN Singer DS TAF7: a possible transcription initiation check-point regulator. Proc Natl Acad Sci U S A (2006) 103(3): 602– 7 10.1073/pnas.0510031103 16407123 PMC1325967 · DOI
  42. [43]Gegonne A Weissman JD Lu H Zhou M Dasgupta A Ribble R TFIID component TAF7 functionally interacts with both TFIIH and P-TEFb. Proc Natl Acad Sci U S A (2008) 105(14): 5367– 72 10.1073/pnas.0801637105 18391197 PMC2291086 · DOI
  43. [44]Devaiah BN Singer DS Cross-talk among RNA polymerase II kinases modulates C-terminal domain phosphorylation. J Biol Chem (2012) 287(46): 38755– 66 10.1074/jbc.M112.412015 23027873 PMC3493918 · DOI
  44. [45]Spilianakis C Papamatheakis J Kretsovali A Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Mol Cell Biol (2000) 20(22): 8489– 98 10.1128/MCB.20.22.8489-8498.2000 11046145 PMC102155 · DOI
  45. [46]Sisk TJ Nickerson K Kwok RP Chang CH Phosphorylation of class II transactivator regulates its interaction ability and transactivation function. Int Immunol (2003) 15(10): 1195– 205 10.1093/intimm/dxg116 13679389 · DOI
  46. [47]Li G Harton JA Zhu X Ting JP Downregulation of CIITA function by protein kinase a (PKA)-mediated phosphorylation: mechanism of prostaglandin E, cyclic AMP, and PKA inhibition of class II major histocompatibility complex expression in monocytic lines. Mol Cell Biol (2001) 21(14): 4626– 35 10.1128/MCB.21.14.4626-4635.2001 11416140 PMC87128 · DOI
  47. [48]Maile T Kwoczynski S Katzenberger RJ Wassarman DA Sauer F TAF1 activates transcription by phosphorylation of serine 33 in histone H2B. Science (2004) 304(5673): 1010– 4 10.1126/science.1095001 15143281 · DOI
  48. [49]Bungard D Fuerth BJ Zeng PY Faubert B Maas NL Viollet B Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science (2010) 329(5996): 1201– 5 10.1126/science.1191241 20647423 PMC3922052 · DOI
  49. [50]Meissner TB Li A Kobayashi KS NLRC5: a newly discovered MHC class I transactivator (CITA). Microbes Infect (2012) 14(6): 477– 84 10.1016/j.micinf.2011.12.007 22209772 PMC3323719 · DOI

Cited by

Sorted by citations

Authors
Devaiah, B. N., & Singer, D. S.
Affiliations
National Institutes of Health (US)
Corresponding author
Singer, Dinah S.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2013
Volume
4
Pages
476-476
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2013.00476
PMC
PMC3868913
OpenAlex
W2161588387
Cited by
127
References
1
Citations by year
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FWCI
3.88
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
CIITA, transcriptional coactivator, enhanceosome, RFX, CREB, NF-Y, TFIID, TAF1, histone acetyltransferase, kinase activity, bare lymphocyte syndrome, interferon-gamma, transcriptional regulation, phosphorylation, protein localization

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