Advertisement

Immunogenetics

, Volume 71, Issue 3, pp 273–282 | Cite as

Class I transactivator, NLRC5: a central player in the MHC class I pathway and cancer immune surveillance

  • Saptha Vijayan
  • Tabasum Sidiq
  • Suhail Yousuf
  • Peter J. van den Elsen
  • Koichi S. KobayashiEmail author
Review
  • 56 Downloads
Part of the following topical collections:
  1. Biology and Evolution of Antigen Presentation

Abstract

Major histocompatibility complex (MHC) class I and class II molecules play critical roles in the activation of the adaptive immune system by presenting antigens to CD8+ and CD4+ T cells, respectively. Although it has been well known that CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, as a master regulator of MHC class II gene expression, the mechanism of MHC class I gene transactivation was unclear. Recently, another NLR protein, NLRC5 (NLR family, CARD domain-containing 5), was identified as an MHC class I transactivator (CITA). NLRC5 is a critical regulator for the transcriptional activation of MHC class I genes and other genes involved in the MHC class I antigen presentation pathway. CITA/NLRC5 plays a crucial role in human cancer immunity through the recruitment and activation of tumor killing CD8+ T cells. Here, we discuss the molecular function and mechanism of CITA/NLRC5 in the MHC class I pathway and its role in cancer.

Keywords

CITA/NLRC5 MHC class I NLR proteins CIITA Cancer 

Notes

Acknowledgements

This work was supported by grants from the American Lung Association, National Multiple Sclerosis Society, Texas A&M Clinical Science & Translational Research Institute, TAM Genomics to KSK.

References

  1. Adams JM, Gerondakis S, Webb E, Corcoran LM, Cory S (1983) Cellular myc oncogene is altered by chromosome translocation to an immunoglobulin locus in murine plasmacytomas and is rearranged similarly in human Burkitt lymphomas. Proc Natl Acad Sci U S A 80:1982–1986.  https://doi.org/10.1073/pnas.80.7.1982 CrossRefGoogle Scholar
  2. Agudo J, Park ES, Rose SA, Alibo E, Sweeney R, Dhainaut M, Kobayashi KS, Sachidanandam R, Baccarini A, Merad M, Brown BD (2018) Quiescent tissue stem cells evade immune surveillance. Immunity 48:271–85 e5.  https://doi.org/10.1016/j.immuni.2018.02.001 CrossRefGoogle Scholar
  3. Benko S, Magalhaes JG, Philpott DJ, Girardin SE (2010) NLRC5 limits the activation of inflammatory pathways. J Immunol 185:1681–1691.  https://doi.org/10.4049/jimmunol.0903900 CrossRefGoogle Scholar
  4. Bewry NN, Bolick SC, Wright KL, Harton JA (2007) GTP-dependent recruitment of CIITA to the class II major histocompatibility complex promoter. J Biol Chem 282:26178–26184.  https://doi.org/10.1074/jbc.M611747200 CrossRefGoogle Scholar
  5. Biswas A, Meissner TB, Kawai T, Kobayashi KS (2012) Cutting edge: impaired MHC class I expression in mice deficient for Nlrc5/class I transactivator. J Immunol 189:516–520.  https://doi.org/10.4049/jimmunol.1200064 CrossRefGoogle Scholar
  6. Chang CH, Fontes JD, Peterlin M, Flavell RA (1994) Class II transactivator (CIITA) is sufficient for the inducible expression of major histocompatibility complex class II genes. J Exp Med 180:1367–1374.  https://doi.org/10.1084/jem.180.4.1367. CrossRefGoogle Scholar
  7. Chang CH, Guerder S, Hong SC, van Ewijk W, Flavell RA (1996) Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity 4:167–178.  https://doi.org/10.1016/S1074-7613(00)80681-0 CrossRefGoogle Scholar
  8. Cressman DE, Chin KC, Taxman DJ, Ting JP (1999) A defect in the nuclear translocation of CIITA causes a form of type II bare lymphocyte syndrome. Immunity 10:163–171.  https://doi.org/10.1016/S1074-7613(00)80017-5 CrossRefGoogle Scholar
  9. Cressman DE, O'Connor WJ, Greer SF, Zhu XS, Ting JP (2001) Mechanisms of nuclear import and export that control the subcellular localization of class II transactivator. J Immunol 167:3626–3634.  https://doi.org/10.4049/jimmunol.167.7.3626 CrossRefGoogle Scholar
  10. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF (2010) NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell 141:483–496.  https://doi.org/10.1016/j.cell.2010.03.040 CrossRefGoogle Scholar
  11. Davis BK, Roberts RA, Huang MT, Willingham SB, Conti BJ, Brickey WJ, Barker BR, Kwan M, Taxman DJ, Accavitti-Loper MA, Duncan JA, Ting JP (2011) Cutting edge: NLRC5-dependent activation of the inflammasome. J Immunol 186:1333–1337.  https://doi.org/10.4049/jimmunol.1003111 CrossRefGoogle Scholar
  12. Downs I, Vijayan S, Sidiq T, Kobayashi KS (2016) CITA/NLRC5: a critical transcriptional regulator of MHC class I gene expression. Biofactors 42:349–357.  https://doi.org/10.1002/biof.1285 CrossRefGoogle Scholar
  13. Durand B, Sperisen P, Emery P, Barras E, Zufferey M, Mach B, Reith W (1997) RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency. EMBO J 16:1045–1055.  https://doi.org/10.1093/emboj/16.5.1045. CrossRefGoogle Scholar
  14. Garrido F, Cabrera T, Aptsiauri N (2010) “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int J Cancer 127:249–256.  https://doi.org/10.1002/ijc.25270. Google Scholar
  15. Germain RN (1994) MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 76:287–299.  https://doi.org/10.1016/0092-8674(94)90336-0 CrossRefGoogle Scholar
  16. Gobin SJ, Peijnenburg A, Keijsers V, van den Elsen PJ (1997) Site alpha is crucial for two routes of IFN gamma-induced MHC class I transactivation: the ISRE-mediated route and a novel pathway involving CIITA. Immunity 6:601–611.  https://doi.org/10.1016/S1074-7613(00)80348-9 CrossRefGoogle Scholar
  17. Gobin SJ, Keijsers V, van Zutphen M, van den Elsen PJ (1998a) The role of enhancer A in the locus-specific transactivation of classical and nonclassical HLA class I genes by nuclear factor kappa B. J Immunol 161:2276–2283Google Scholar
  18. Gobin SJ, Peijnenburg A, van Eggermond M, van Zutphen M, van den Berg R, van den Elsen PJ (1998b) The RFX complex is crucial for the constitutive and CIITA-mediated transactivation of MHC class I and beta2-microglobulin genes. Immunity 9:531–541.  https://doi.org/10.1016/S1074-7613(00)80636-6 CrossRefGoogle Scholar
  19. Gobin SJ, van Zutphen M, Woltman AM, van den Elsen PJ (1999) Transactivation of classical and nonclassical HLA class I genes through the IFN-stimulated response element. J Immunol 163:1428–1434Google Scholar
  20. Gobin SJ, van Zutphen M, Westerheide SD, Boss JM, van den Elsen PJ (2001) The MHC-specific enhanceosome and its role in MHC class I and beta(2)-microglobulin gene transactivation. J Immunol 167:5175–5184.  https://doi.org/10.4049/jimmunol.167.9.5175 CrossRefGoogle Scholar
  21. Guo X, Liu T, Shi H, Wang J, Ji P, Wang H, Hou Y, Tan RX, Li E (2015) Respiratory syncytial virus infection upregulates NLRC5 and major histocompatibility complex class I expression through RIG-I induction in airway epithelial cells. J Virol 89:7636–7645.  https://doi.org/10.1128/JVI.00349-15 CrossRefGoogle Scholar
  22. Gutte PG, Jurt S, Grutter MG, Zerbe O (2014) Unusual structural features revealed by the solution NMR structure of the NLRC5 caspase recruitment domain. Biochemistry 53:3106–3117.  https://doi.org/10.1021/bi500177x CrossRefGoogle Scholar
  23. Harton JA, Cressman DE, Chin KC, Der CJ, Ting JP (1999) GTP binding by class II transactivator: role in nuclear import. Science 285:1402–1405CrossRefGoogle Scholar
  24. Hastings PJ, Lupski JR, Rosenberg SM, Ira G (2009) Mechanisms of change in gene copy number. Nat Rev Genet 10:551–564.  https://doi.org/10.1038/nrg2593 CrossRefGoogle Scholar
  25. Hu Y (2015) A feedforward loop of NLRC5 (de)ubiquitination keeps IKK-NF-kappaB in check. J Cell Biol 211:941–943.  https://doi.org/10.1083/jcb.201511039 CrossRefGoogle Scholar
  26. Itoh-Lindstrom Y, Piskurich JF, Felix NJ, Wang Y, Brickey WJ, Platt JL, Koller BH, Ting JP (1999) Reduced IL-4-, lipopolysaccharide-, and IFN-gamma-induced MHC class II expression in mice lacking class II transactivator due to targeted deletion of the GTP-binding domain. J Immunol 163:2425–2431Google Scholar
  27. Koopman LA, Corver WE, van der Slik AR, Giphart MJ, Fleuren GJ (2000) Multiple genetic alterations cause frequent and heterogeneous human histocompatibility leukocyte antigen class I loss in cervical cancer. J Exp Med 191:961–976.  https://doi.org/10.1084/jem.191.6.961 CrossRefGoogle Scholar
  28. Kuenzel S, Till A, Winkler M, Hasler R, Lipinski S, Jung S, Grotzinger J, Fickenscher H, Schreiber S, Rosenstiel P (2010) The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses. J Immunol 184:1990–2000.  https://doi.org/10.4049/jimmunol.0900557 CrossRefGoogle Scholar
  29. Kumar H, Pandey S, Zou J, Kumagai Y, Takahashi K, Akira S, Kawai T (2011) NLRC5 deficiency does not influence cytokine induction by virus and bacteria infections. J Immunol 186:994–1000.  https://doi.org/10.4049/jimmunol.1002094 CrossRefGoogle Scholar
  30. Ludigs K, Seguin-Estevez Q, Lemeille S, Ferrero I, Rota G, Chelbi S, Mattmann C, MacDonald HR, Reith W, Guarda G (2015) NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module. PLoS Genet 11:e1005088.  https://doi.org/10.1371/journal.pgen.1005088 CrossRefGoogle Scholar
  31. Lupfer CR, Stokes KL, Kuriakose T, Kanneganti TD (2017) Deficiency of the NOD-like receptor NLRC5 results in decreased CD8(+) T cell function and impaired viral clearance. J Virol 91.  https://doi.org/10.1128/JVI.00377-17
  32. Maleno I, Lopez-Nevot MA, Cabrera T, Salinero J, Garrido F (2002) Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Cancer Immunol Immunother 51:389–396.  https://doi.org/10.1007/s00262-002-0296-0 CrossRefGoogle Scholar
  33. Martin BK, Chin KC, Olsen JC, Skinner CA, Dey A, Ozato K, Ting JP (1997) Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 6:591–600CrossRefGoogle Scholar
  34. Masternak K, Barras E, Zufferey M, Conrad B, Corthals G, Aebersold R, Sanchez JC, Hochstrasser DF, Mach B, Reith W (1998) A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nat Genet 20:273–277.  https://doi.org/10.1038/3081 CrossRefGoogle Scholar
  35. Masternak K, Muhlethaler-Mottet A, Villard J, Zufferey M, Steimle V, Reith W (2000) CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with an enhanceosome complex. Genes Dev 14:1156–1166.  https://doi.org/10.1101/gad.14.9.1156. Google Scholar
  36. Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E, Iliopoulos D, van den Elsen PJ, Kobayashi KS (2010) NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci U S A 107:13794–13799.  https://doi.org/10.1073/pnas.1008684107 CrossRefGoogle Scholar
  37. Meissner TB, Li A, Kobayashi KS (2012a) NLRC5: a newly discovered MHC class I transactivator (CITA). Microbes Infect 14:477–484.  https://doi.org/10.1016/j.micinf.2011.12.007 CrossRefGoogle Scholar
  38. Meissner TB, Li A, Liu YJ, Gagnon E, Kobayashi KS (2012b) The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity. Biochem Biophys Res Commun 418:786–791.  https://doi.org/10.1016/j.bbrc.2012.01.104 CrossRefGoogle Scholar
  39. Meissner TB, Liu YJ, Lee KH, Li A, Biswas A, van Eggermond MC, van den Elsen PJ, Kobayashi KS (2012c) NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. J Immunol 188:4951–4958.  https://doi.org/10.4049/jimmunol.1103160 CrossRefGoogle Scholar
  40. Meng Q, Cai C, Sun T, Wang Q, Xie W, Wang R, Cui J (2015) Reversible ubiquitination shapes NLRC5 function and modulates NF-kappaB activation switch. J Cell Biol 211:1025–1040.  https://doi.org/10.1083/jcb.201505091 CrossRefGoogle Scholar
  41. Nagarajan UM, Louis-Plence P, DeSandro A, Nilsen R, Bushey A, Boss JM (1999) RFX-B is the gene responsible for the most common cause of the bare lymphocyte syndrome, an MHC class II immunodeficiency. Immunity 10:153–162.  https://doi.org/10.1016/S1074-7613(00)80016-3 CrossRefGoogle Scholar
  42. Nair-Gupta P, Baccarini A, Tung N, Seyffer F, Florey O, Huang Y, Banerjee M, Overholtzer M, Roche PA, Tampe R, Brown BD, Amsen D, Whiteheart SW, Blander JM (2014) TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation. Cell 158:506–521.  https://doi.org/10.1016/j.cell.2014.04.054 CrossRefGoogle Scholar
  43. Neerincx A, Lautz K, Menning M, Kremmer E, Zigrino P, Hosel M, Buning H, Schwarzenbacher R, Kufer TA (2010) A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses. J Biol Chem 285:26223–26232.  https://doi.org/10.1074/jbc.M110.109736 CrossRefGoogle Scholar
  44. Neerincx A, Rodriguez GM, Steimle V, Kufer TA (2012) NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner. J Immunol 188:4940–4950.  https://doi.org/10.4049/jimmunol.1103136 CrossRefGoogle Scholar
  45. Nickerson K, Sisk TJ, Inohara N, Yee CS, Kennell J, Cho MC, Yannie PJ 2nd, Nunez G, Chang CH (2001) Dendritic cell-specific MHC class II transactivator contains a caspase recruitment domain that confers potent transactivation activity. J Biol Chem 276:19089–19093.  https://doi.org/10.1074/jbc.M101295200 CrossRefGoogle Scholar
  46. Ozcan M, Janikovits J, von Knebel Doeberitz M, Kloor M (2018) Complex pattern of immune evasion in MSI colorectal cancer. Oncoimmunology 7:e1445453.  https://doi.org/10.1080/2162402X.2018.1445453 CrossRefGoogle Scholar
  47. Paschen A, Mendez RM, Jimenez P, Sucker A, Ruiz-Cabello F, Song M, Garrido F, Schadendorf D (2003) Complete loss of HLA class I antigen expression on melanoma cells: a result of successive mutational events. Int J Cancer 103:759–767.  https://doi.org/10.1002/ijc.10906 CrossRefGoogle Scholar
  48. Ranjan P, Singh N, Kumar A, Neerincx A, Kremmer E, Cao W, Davis WG, Katz JM, Gangappa S, Lin R, Kufer TA, Sambhara S (2015) NLRC5 interacts with RIG-I to induce a robust antiviral response against influenza virus infection. Eur J Immunol 45:758–772.  https://doi.org/10.1002/eji.201344412 CrossRefGoogle Scholar
  49. Reith W, Mach B (2001) The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol 19:331–373.  https://doi.org/10.1146/annurev.immunol.19.1.331 CrossRefGoogle Scholar
  50. Reith W, Satola S, Sanchez CH, Amaldi I, Lisowska-Grospierre B, Griscelli C, Hadam MR, Mach B (1988) Congenital immunodeficiency with a regulatory defect in MHC class II gene expression lacks a specific HLA-DR promoter binding protein, RF-X. Cell 53:897–906.  https://doi.org/10.1016/S0092-8674(88)90389-3 CrossRefGoogle Scholar
  51. Robbins GR, Truax AD, Davis BK, Zhang L, Brickey WJ, Ting JP (2012) Regulation of class I major histocompatibility complex (MHC) by nucleotide-binding domain, leucine-rich repeat-containing (NLR) proteins. J Biol Chem 287:24294–24303.  https://doi.org/10.1074/jbc.M112.364604 CrossRefGoogle Scholar
  52. Rodriguez GM, Bobbala D, Serrano D, Mayhue M, Champagne A, Saucier C, Steimle V, Kufer TA, Menendez A, Ramanathan S, Ilangumaran S (2016) NLRC5 elicits antitumor immunity by enhancing processing and presentation of tumor antigens to CD8(+) T lymphocytes. Oncoimmunology 5:e1151593.  https://doi.org/10.1080/2162402X.2016.1151593 CrossRefGoogle Scholar
  53. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570.  https://doi.org/10.1126/science.1203486 CrossRefGoogle Scholar
  54. Spilianakis C, Papamatheakis J, Kretsovali A (2000) Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Mol Cell Biol 20:8489–8498.  https://doi.org/10.1128/MCB.20.22.8489-8498.2000 CrossRefGoogle Scholar
  55. Staehli F, Ludigs K, Heinz LX, Seguin-Estevez Q, Ferrero I, Braun M, Schroder K, Rebsamen M, Tardivel A, Mattmann C, MacDonald HR, Romero P, Reith W, Guarda G, Tschopp J (2012) NLRC5 deficiency selectively impairs MHC class I- dependent lymphocyte killing by cytotoxic T cells. J Immunol 188:3820–3828.  https://doi.org/10.4049/jimmunol.1102671 CrossRefGoogle Scholar
  56. Steimle V, Otten LA, Zufferey M, Mach B (1993) Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 75:135–146CrossRefGoogle Scholar
  57. Steimle V, Durand B, Barras E, Zufferey M, Hadam MR, Mach B, Reith W (1995) A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev 9:1021–1032.  https://doi.org/10.1101/gad.9.9.1021 CrossRefGoogle Scholar
  58. Ting JP, Trowsdale J (2002) Genetic control of MHC class II expression. Cell 109(109 Suppl):S21–S33.  https://doi.org/10.1016/S0092-8674(02)00696-7 CrossRefGoogle Scholar
  59. van den Elsen PJ (2011) Expression regulation of major histocompatibility complex class I and class II encoding genes. Front Immunol 2:48.  https://doi.org/10.3389/fimmu.2011.00048 Google Scholar
  60. Yao Y, Wang Y, Chen F, Huang Y, Zhu S, Leng Q, Wang H, Shi Y, Qian Y (2012) NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens. Cell Res 22:836–847.  https://doi.org/10.1038/cr.2012.56 CrossRefGoogle Scholar
  61. Yoshihama S, Roszik J, Downs I, Meissner TB, Vijayan S, Chapuy B, Sidiq T, Shipp MA, Lizee GA, Kobayashi KS (2016) NLRC5/MHC class I transactivator is a target for immune evasion in cancer. Proc Natl Acad Sci U S A 113:5999–6004.  https://doi.org/10.1073/pnas.1602069113 CrossRefGoogle Scholar
  62. Yoshihama S, Vijayan S, Sidiq T, Kobayashi KS (2017) NLRC5/CITA: a key player in cancer immune surveillance. Trends Cancer 3:28–38.  https://doi.org/10.1016/j.trecan.2016.12.003 CrossRefGoogle Scholar
  63. Zhu XS, Linhoff MW, Li G, Chin KC, Maity SN, Ting JP (2000) 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 20:6051–6061.  https://doi.org/10.1128/MCB.20.16.6051-6061.2000 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Microbial Pathogenesis and ImmunologyTexas A&M Health Science CenterCollege StationUSA
  2. 2.Department of Immunohematology and Blood TransfusionLeiden University Medical CenterLeidenThe Netherlands
  3. 3.Department of PathologyVU University Medical CenterAmsterdamThe Netherlands
  4. 4.Department of ImmunologyHokkaido University Graduate School of MedicineSapporoJapan

Personalised recommendations