Expression regulation and function of NLRC5

Abstract

The NOD like receptors (NLRs), a class of intracellular receptors that respond to pathogen attack or cellular stress, have gained increasing attention. NLRC5, the largest member of the NLR protein family, has recently been identified as a critical regulator of immune responses. While NLRC5 is constitutively and widely expressed, it can be dramatically induced by interferons during pathogen infections. Both in vitro and in vivo studies have demonstrated that NLRC5 is a specific and master regulator of major mistocompatibility complex (MHC) class I genes as well as related genes involved in MHC class I antigen presentation. The expression of MHC class I genes is regulated by NLRC5 in coordination with the RFX components through an enhanceosome-dependent manner. And the involvement of NLRC5 in MHC class I mediated CD8+ T cell activation, proliferation and cytotoxicity is proved to be critical for host defense against intracellular bacterial infections. Nevertheless, the role of NLRC5 in innate immunity remains to be further explored. Here, we review the research advances on the structure, expression regulation and function of NLRC5.

References

  1. Allen, I.C., Wilson, J.E., Schneider, M., Lich, J.D., Roberts, R.A., Arthur, J.C., Woodford, R.M., Davis, B.K., Uronis, J.M., Herfarth, H.H., et al. (2012). NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity 36, 742–754.

    Article  Google Scholar 

  2. Anand, P.K., Malireddi, R.K., Lukens, J.R., Vogel, P., Bertin, J., Lamkanfi, M., and Kanneganti, T.D. (2012). NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488, 389–393.

    Article  Google Scholar 

  3. Benko, S., Magalhaes, J.G., Philpott, D.J., and Girardin, S.E. (2010). NLRC5 limits the activation of inflammatory pathways. J Immunol 185, 1681–1691.

    Article  Google Scholar 

  4. Biswas, A., Meissner, T.B., Kawai, T., and Kobayashi, K.S. (2012). Cutting edge: impaired MHC class I expression in mice deficient for nlrc5/class I transactivator. J Immunol 189, 516–520.

    Article  Google Scholar 

  5. Camacho-Carvajal, M.M., Klingler, S., Schnappauf, F., Hake, S.B., and Steimle, V. (2004). Importance of class II transactivator leucinerich repeats for dominant-negative function and nucleo-cytoplasmic transport. Int Immunol 16, 65–75.

    Article  Google Scholar 

  6. Chang, C.H., Guerder, S., Hong, S.C., van Ewijk, W., and Flavell, R.A. (1996). Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity 4, 167–178.

    Article  Google Scholar 

  7. Cui, J., Li, Y., Zhu, L., Liu, D., Songyang, Z., Wang, H.Y., and Wang, R.F. (2012). NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4. Nat Immunol 13, 387–395.

    Article  Google Scholar 

  8. Cui, J., Zhu, L., Xia, X., Wang, H.Y., Legras, X., Hong, J., Ji, J., Shen, P., Zheng, S., Chen, Z.J., et al. (2010). NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell 141, 483–496.

    Article  Google Scholar 

  9. Davis, B.K., Roberts, R.A., Huang, M.T., Willingham, S.B., Conti, B.J., Brickey, W.J., Barker, B.R., Kwan, M., Taxman, D.J., Accavitti-Loper, M.A., et al. (2011). Cutting Edge: NLRC5-Dependent Activation of the Inflammasome. J Immunol 186, 1333–1337.

    Article  Google Scholar 

  10. Eisenbarth, S.C., Williams, A., Colegio, O.R., Meng, H., Strowig, T., Rongvaux, A., Henao-Mejia, J., Thaiss, C.A., Joly, S., Gonzalez, D.G., et al. (2012). NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature 484, 510–513.

    Article  Google Scholar 

  11. Elinav, E., Strowig, T., Kau, A.L., Henao-Mejia, J., Thaiss, C.A., Booth, C.J., Peaper, D.R., Bertin, J., Eisenbarth, S.C., Gordon, J.I., et al. (2011). NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757.

    Article  Google Scholar 

  12. Gong, Y.N., and Shao, F. (2012). Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation. Protein Cell 3, 98–105.

    Article  Google Scholar 

  13. Hake, S.B., Masternak, K., Kammerbauer, C., Janzen, C., Reith, W., and Steimle, V. (2000). 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 20, 7716–7725.

    Article  Google Scholar 

  14. Jabrane-Ferrat, N., Nekrep, N., Tosi, G., Esserman, L., and Peterlin, B.M. (2003). MHC class II enhanceosome: how is the class II transactivator recruited to DNA-bound activators? Int Immunol 15, 467–475.

    Article  Google Scholar 

  15. Jiang, H., and Chess, L. (2000). The specific regulation of immune responses by CD8+ T cells restricted by the MHC class IB molecule, QA-1. Annu Rev Immunol 18, 185–216.

    Article  Google Scholar 

  16. Jounai, N., Kobiyama, K., Shiina, M., Ogata, K., Ishii, K.J., and Takeshita, F. (2011). NLRP4 negatively regulates autophagic processes through an association with beclin1. J Immunol 186, 1646–1655.

    Article  Google Scholar 

  17. Khare, S., Dorfleutner, A., Bryan, N.B., Yun, C., Radian, A.D., de Almeida, L., Rojanasakul, Y., and Stehlik, C. (2012). An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 36, 464–476.

    Article  Google Scholar 

  18. Kobayashi, K.S., and van den Elsen, P.J. (2012). NLRC5: a key regulator of MHC class I-dependent immune responses. Nat Rev Immunol 12, 813–820.

    Article  Google Scholar 

  19. Kuenzel, S., Till, A., Winkler, M., Hasler, R., Lipinski, S., Jung, S., Grotzinger, J., Fickenscher, H., Schreiber, S., and Rosenstiel, P. (2010). The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses. J Immunol 184, 1990–2000.

    Article  Google Scholar 

  20. Kumar, H., Pandey, S., Zou, J., Kumagai, Y., Takahashi, K., Akira, S., and Kawai, T. (2011). NLRC5 deficiency does not influence cytokine induction by virus and bacteria infections. J Immunol 186, 994–1000.

    Article  Google Scholar 

  21. Lamkanfi, M., and Kanneganti, T.D. (2012). Regulation of immune pathways by the NOD-like receptor NLRC5. Immunobiology 217, 13–16.

    Article  Google Scholar 

  22. LeibundGut-Landmann, S., Waldburger, J.M., Krawczyk, M., Otten, L.A., Suter, T., Fontana, A., Acha-Orbea, H., and Reith, W. (2004). Mini-review: specificity and expression of CIITA, the master regulator of MHC class II genes. Eur J Immunol 34, 1513–1525.

    Article  Google Scholar 

  23. Levinsohn, J.L., Newman, Z.L., Hellmich, K.A., Fattah, R., Getz, M.A., Liu, S., Sastalla, I., Leppla, S.H., and Moayeri, M. (2012). Anthrax lethal factor cleavage of Nlrp1 is required for activation of the in-flammasome. PLoS Pathog 8, e1002638.

    Article  Google Scholar 

  24. Lie, B.A., and Thorsby, E. (2005). Several genes in the extended human MHC contribute to predisposition to autoimmune diseases. Curr Opin Immunol 17, 526–531.

    Article  Google Scholar 

  25. Martin, B.K., Chin, K. C., Olsen, J.C., Skinner, C.A., Dey, A., Ozato, K., and Ting, J.P.Y. (1997). Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity 6, 591–600.

    Article  Google Scholar 

  26. Martinon, F., Mayor, A., and Tschopp, J. (2009). The inflammasomes: guardians of the body. Annu Rev Immunol 27, 229–265.

    Article  Google Scholar 

  27. Masternak, K., and Reith, W. (2002). Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation. Embo Journal 21, 1379–1388.

    Article  Google Scholar 

  28. Meissner, T.B., Li, A., Biswas, A., Lee, K.H., Liu, Y.J., Bayir, E., Iliopoulos, D., van den Elsen, P.J., and Kobayashi, K.S. (2010). NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci U S A 107, 13794–13799.

    Article  Google Scholar 

  29. Meissner, T.B., Li, A., Liu, Y.J., Gagnon, E., and Kobayashi, K.S. (2012a). The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity. Biochem Biophys Res Commun 418, 786–791.

    Article  Google Scholar 

  30. Meissner, T.B., Liu, Y.J., Lee, K.H., Li, A., Biswas, A., van Eggermond, M.C., van den Elsen, P.J., and Kobayashi, K.S. (2012b). NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. J Immunol 188, 4951–4958.

    Article  Google Scholar 

  31. Moreno, C.S., Beresford, G.W., Louis-Plence, P., Morris, A.C., and Boss, J.M. (1999). CREB regulates MHC class II expression in a CIITA-dependent manner. Immunity 10, 143–151.

    Article  Google Scholar 

  32. Neerincx, A., Lautz, K., Menning, M., Kremmer, E., Zigrino, P., Hosel, M., Buning, H., Schwarzenbacher, R., and Kufer, T.A. (2010). A role for the human NLR family member NLRC5 in antiviral responses. J Biol Chem 285, 26223–26232.

    Article  Google Scholar 

  33. Neerincx, A., Rodriguez, G.M., Steimle, V., and Kufer, T.A. (2012). NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner. J Immunol 188, 4940–4950.

    Article  Google Scholar 

  34. Pamer, E., and Cresswell, P. (1998). Mechanisms of MHC class I — Restricted antigen processing. Ann Rev Immunol 16, 323–358.

    Article  Google Scholar 

  35. Peaper, D.R., and Cresswell, P. (2008). Regulation of MHC Class I Assembly and Peptide Binding. Annu Rev Cell Dev Bi 24, 343–368.

    Article  Google Scholar 

  36. Robbins, G.R., Truax, A.D., Davis, B.K., Zhang, L., Brickey, W.J., and Ting, J.P. (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.

    Article  Google Scholar 

  37. Savage, P.A., Boniface, J.J., and Davis, M.M. (1999). A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity 10, 485–492.

    Article  Google Scholar 

  38. Schneider, M., Zimmermann, A.G., Roberts, R.A., Zhang, L., Swanson, K.V., Wen, H., Davis, B.K., Allen, I.C., Holl, E.K., Ye, Z., et al. (2012). The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-kappaB. Nat Immunol 13, 823–831.

    Article  Google Scholar 

  39. Schroder, K., and Tschopp, J. (2010). The inflammasomes. Cell 140, 821–832.

    Article  Google Scholar 

  40. Shepherd, J.C., Schumacher, T.N.M., Ashtonrickardt, P.G., Imaeda, S., Ploegh, H.L., Janeway, C.A., and Tonegawa, S. (1993). Tap1-Dependent Peptide Translocation in-Vitro Is Atp-Dependent and Peptide Selective. Cell 74, 577–584.

    Article  Google Scholar 

  41. Staehli, F., Ludigs, K., Heinz, L.X., Seguin-Estevez, Q., Ferrero, I., Braun, M., Schroder, K., Rebsamen, M., Tardivel, A., Mattmann, C., et al. (2012). NLRC5 deficiency selectively impairs MHC class I-dependent lymphocyte killing by cytotoxic T cells. J Immunol 188, 3820–3828.

    Article  Google Scholar 

  42. Strober, W., Murray, P.J., Kitani, A., and Watanabe, T. (2006). Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 6, 9–20.

    Article  Google Scholar 

  43. Tong, Y., Cui, J., Li, Q., Zou, J., Wang, H.Y., and Wang, R.F. (2012). Enhanced TLR-induced NF-kappaB signaling and type I interferon responses in NLRC5 deficient mice. Cell Res 22, 822–835.

    Article  Google Scholar 

  44. Tschopp, J., and Schroder, K. (2010). NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 10, 210–215.

    Article  Google Scholar 

  45. Vesely, M.D., Kershaw, M.H., Schreiber, R.D., and Smyth, M.J. (2011). Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29, 235–271.

    Article  Google Scholar 

  46. Vladimer, G.I., Weng, D., Paquette, S.W., Vanaja, S.K., Rathinam, V.A., Aune, M.H., Conlon, J.E., Burbage, J.J., Proulx, M.K., Liu, Q., et al. (2012). The NLRP12 Inflammasome Recognizes Yersinia pestis. Immunity 37, 96–107.

    Article  Google Scholar 

  47. Williams, G.S., Malin, M., Vremec, D., Chang, C.H., Boyd, R., Benoist, C., and Mathis, D. (1998). Mice lacking the transcription factor CIITA—a second look. Int Immunol 10, 1957–1967.

    Article  Google Scholar 

  48. Williams, K.L., Taxman, D.J., Linhoff, M.W., Reed, W., and Ting, J.P.Y. (2003). Cutting edge: Monarch-1: A pyrin/nucleotide-binding domain/leucine-rich repeat protein that controls classical and nonclassical MHC class I genes. Journal of Immunology 170, 5354–5358.

    Article  Google Scholar 

  49. Yao, Y., Wang, Y., Chen, F., Huang, Y., Zhu, S., Leng, Q., Wang, H., Shi, Y., and Qian, Y. (2012). NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens. Cell Res 22, 836–847.

    Article  Google Scholar 

  50. Zaki, M.H., Vogel, P., Malireddi, R.K., Body-Malapel, M., Anand, P.K., Bertin, J., Green, D.R., Lamkanfi, M., and Kanneganti, T.D. (2011). The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20, 649–660.

    Article  Google Scholar 

  51. Zhao, Y., and Shao, F. (2012). NLRC5: a NOD-like receptor protein with many faces in immune regulation. Cell Res 22, 1099–1101.

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Youcun Qian.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yao, Y., Qian, Y. Expression regulation and function of NLRC5. Protein Cell 4, 168–175 (2013). https://doi.org/10.1007/s13238-012-2109-3

Download citation

Keywords

  • NLR
  • NLRC5
  • MHC Class I