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.
Keywords: NLR, NLRC5, MHC Class I
References
- Allen IC, Wilson JE, Schneider M, Lich JD, Roberts RA, Arthur JC, Woodford RM, Davis BK, Uronis JM, Herfarth HH, et al. NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity. 2012;36:742–754. doi: 10.1016/j.immuni.2012.03.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anand PK, Malireddi RK, Lukens JR, Vogel P, Bertin J, Lamkanfi M, Kanneganti TD. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature. 2012;488:389–393. doi: 10.1038/nature11250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Benko S, Magalhaes JG, Philpott DJ, Girardin SE. NLRC5 limits the activation of inflammatory pathways. J Immunol. 2010;185:1681–1691. doi: 10.4049/jimmunol.0903900. [DOI] [PubMed] [Google Scholar]
- Biswas A, Meissner TB, Kawai T, Kobayashi KS. Cutting edge: impaired MHC class I expression in mice deficient for nlrc5/class I transactivator. J Immunol. 2012;189:516–520. doi: 10.4049/jimmunol.1200064. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Camacho-Carvajal MM, Klingler S, Schnappauf F, Hake SB, Steimle V. Importance of class II transactivator leucinerich repeats for dominant-negative function and nucleo-cytoplasmic transport. Int Immunol. 2004;16:65–75. doi: 10.1093/intimm/dxh010. [DOI] [PubMed] [Google Scholar]
- Chang CH, Guerder S, Hong SC, van Ewijk W, Flavell RA. Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity. 1996;4:167–178. doi: 10.1016/S1074-7613(00)80681-0. [DOI] [PubMed] [Google Scholar]
- Cui J, Li Y, Zhu L, Liu D, Songyang Z, Wang HY, Wang RF. NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4. Nat Immunol. 2012;13:387–395. doi: 10.1038/ni.2239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, et al. NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell. 2010;141:483–496. doi: 10.1016/j.cell.2010.03.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davis BK, Roberts RA, Huang MT, Willingham SB, Conti BJ, Brickey WJ, Barker BR, Kwan M, Taxman DJ, Accavitti-Loper MA, et al. Cutting Edge: NLRC5-Dependent Activation of the Inflammasome. J Immunol. 2011;186:1333–1337. doi: 10.4049/jimmunol.1003111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eisenbarth SC, Williams A, Colegio OR, Meng H, Strowig T, Rongvaux A, Henao-Mejia J, Thaiss CA, Joly S, Gonzalez DG, et al. NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature. 2012;484:510–513. doi: 10.1038/nature11012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 2011;145:745–757. doi: 10.1016/j.cell.2011.04.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gong YN, Shao F. Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation. Protein Cell. 2012;3:98–105. doi: 10.1007/s13238-012-2028-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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;20:7716–7725. doi: 10.1128/MCB.20.20.7716-7725.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jabrane-Ferrat N, Nekrep N, Tosi G, Esserman L, Peterlin BM. MHC class II enhanceosome: how is the class II transactivator recruited to DNA-bound activators? Int Immunol. 2003;15:467–475. doi: 10.1093/intimm/dxg048. [DOI] [PubMed] [Google Scholar]
- Jiang H, Chess L. The specific regulation of immune responses by CD8+ T cells restricted by the MHC class IB molecule, QA-1. Annu Rev Immunol. 2000;18:185–216. doi: 10.1146/annurev.immunol.18.1.185. [DOI] [PubMed] [Google Scholar]
- Jounai N, Kobiyama K, Shiina M, Ogata K, Ishii KJ, Takeshita F. NLRP4 negatively regulates autophagic processes through an association with beclin1. J Immunol. 2011;186:1646–1655. doi: 10.4049/jimmunol.1001654. [DOI] [PubMed] [Google Scholar]
- Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, Rojanasakul Y, Stehlik C. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity. 2012;36:464–476. doi: 10.1016/j.immuni.2012.02.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kobayashi KS, van den Elsen PJ. NLRC5: a key regulator of MHC class I-dependent immune responses. Nat Rev Immunol. 2012;12:813–820. doi: 10.1038/nri3339. [DOI] [PubMed] [Google Scholar]
- Kuenzel S, Till A, Winkler M, Hasler R, Lipinski S, Jung S, Grotzinger J, Fickenscher H, Schreiber S, Rosenstiel P. The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses. J Immunol. 2010;184:1990–2000. doi: 10.4049/jimmunol.0900557. [DOI] [PubMed] [Google Scholar]
- Kumar H, Pandey S, Zou J, Kumagai Y, Takahashi K, Akira S, Kawai T. NLRC5 deficiency does not influence cytokine induction by virus and bacteria infections. J Immunol. 2011;186:994–1000. doi: 10.4049/jimmunol.1002094. [DOI] [PubMed] [Google Scholar]
- Lamkanfi M, Kanneganti TD. Regulation of immune pathways by the NOD-like receptor NLRC5. Immunobiology. 2012;217:13–16. doi: 10.1016/j.imbio.2011.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LeibundGut-Landmann S, Waldburger JM, Krawczyk M, Otten LA, Suter T, Fontana A, Acha-Orbea H, Reith W. Mini-review: specificity and expression of CIITA, the master regulator of MHC class II genes. Eur J Immunol. 2004;34:1513–1525. doi: 10.1002/eji.200424964. [DOI] [PubMed] [Google Scholar]
- Levinsohn JL, Newman ZL, Hellmich KA, Fattah R, Getz MA, Liu S, Sastalla I, Leppla SH, Moayeri M. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the in-flammasome. PLoS Pathog. 2012;8:e1002638. doi: 10.1371/journal.ppat.1002638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lie BA, Thorsby E. Several genes in the extended human MHC contribute to predisposition to autoimmune diseases. Curr Opin Immunol. 2005;17:526–531. doi: 10.1016/j.coi.2005.07.001. [DOI] [PubMed] [Google Scholar]
- Martin BK, Chin K C, Olsen JC, Skinner CA, Dey A, Ozato K, Ting JPY. Induction of MHC class I expression by the MHC class II transactivator CIITA. Immunity. 1997;6:591–600. doi: 10.1016/S1074-7613(00)80347-7. [DOI] [PubMed] [Google Scholar]
- Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–265. doi: 10.1146/annurev.immunol.021908.132715. [DOI] [PubMed] [Google Scholar]
- Masternak K, Reith W. Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation. Embo Journal. 2002;21:1379–1388. doi: 10.1093/emboj/21.6.1379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E, Iliopoulos D, van den Elsen PJ, Kobayashi KS. NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci U S A. 2010;107:13794–13799. doi: 10.1073/pnas.1008684107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meissner TB, Li A, Liu YJ, Gagnon E, Kobayashi KS. The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity. Biochem Biophys Res Commun. 2012;418:786–791. doi: 10.1016/j.bbrc.2012.01.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meissner TB, Liu YJ, Lee KH, Li A, Biswas A, van Eggermond MC, van den Elsen PJ, Kobayashi KS. NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. J Immunol. 2012;188:4951–4958. doi: 10.4049/jimmunol.1103160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moreno CS, Beresford GW, Louis-Plence P, Morris AC, Boss JM. CREB regulates MHC class II expression in a CIITA-dependent manner. Immunity. 1999;10:143–151. doi: 10.1016/S1074-7613(00)80015-1. [DOI] [PubMed] [Google Scholar]
- Neerincx A, Lautz K, Menning M, Kremmer E, Zigrino P, Hosel M, Buning H, Schwarzenbacher R, Kufer TA. A role for the human NLR family member NLRC5 in antiviral responses. J Biol Chem. 2010;285:26223–26232. doi: 10.1074/jbc.M110.109736. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Neerincx A, Rodriguez GM, Steimle V, Kufer TA. NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner. J Immunol. 2012;188:4940–4950. doi: 10.4049/jimmunol.1103136. [DOI] [PubMed] [Google Scholar]
- Pamer E, Cresswell P. Mechanisms of MHC class I — Restricted antigen processing. Ann Rev Immunol. 1998;16:323–358. doi: 10.1146/annurev.immunol.16.1.323. [DOI] [PubMed] [Google Scholar]
- Peaper DR, Cresswell P. Regulation of MHC Class I Assembly and Peptide Binding. Annu Rev Cell Dev Bi. 2008;24:343–368. doi: 10.1146/annurev.cellbio.24.110707.175347. [DOI] [PubMed] [Google Scholar]
- Robbins GR, Truax AD, Davis BK, Zhang L, Brickey WJ, Ting JP. Regulation of class I major histocompatibility complex (MHC) by nucleotide-binding domain, leucine-rich repeat-containing (NLR) proteins. J Biol Chem. 2012;287:24294–24303. doi: 10.1074/jbc.M112.364604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Savage PA, Boniface JJ, Davis MM. A kinetic basis for T cell receptor repertoire selection during an immune response. Immunity. 1999;10:485–492. doi: 10.1016/S1074-7613(00)80048-5. [DOI] [PubMed] [Google Scholar]
- Schneider M, Zimmermann AG, Roberts RA, Zhang L, Swanson KV, Wen H, Davis BK, Allen IC, Holl EK, Ye Z, et al. The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-kappaB. Nat Immunol. 2012;13:823–831. doi: 10.1038/ni.2378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–832. doi: 10.1016/j.cell.2010.01.040. [DOI] [PubMed] [Google Scholar]
- Shepherd JC, Schumacher TNM, Ashtonrickardt PG, Imaeda S, Ploegh HL, Janeway CA, Tonegawa S. Tap1-Dependent Peptide Translocation in-Vitro Is Atp-Dependent and Peptide Selective. Cell. 1993;74:577–584. doi: 10.1016/0092-8674(93)80058-M. [DOI] [PubMed] [Google Scholar]
- Staehli F, Ludigs K, Heinz LX, Seguin-Estevez Q, Ferrero I, Braun M, Schroder K, Rebsamen M, Tardivel A, Mattmann C, et al. NLRC5 deficiency selectively impairs MHC class I-dependent lymphocyte killing by cytotoxic T cells. J Immunol. 2012;188:3820–3828. doi: 10.4049/jimmunol.1102671. [DOI] [PubMed] [Google Scholar]
- Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol. 2006;6:9–20. doi: 10.1038/nri1747. [DOI] [PubMed] [Google Scholar]
- Tong Y, Cui J, Li Q, Zou J, Wang HY, Wang RF. Enhanced TLR-induced NF-kappaB signaling and type I interferon responses in NLRC5 deficient mice. Cell Res. 2012;22:822–835. doi: 10.1038/cr.2012.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tschopp J, Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10:210–215. doi: 10.1038/nri2725. [DOI] [PubMed] [Google Scholar]
- Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235–271. doi: 10.1146/annurev-immunol-031210-101324. [DOI] [PubMed] [Google Scholar]
- Vladimer GI, Weng D, Paquette SW, Vanaja SK, Rathinam VA, Aune MH, Conlon JE, Burbage JJ, Proulx MK, Liu Q, et al. The NLRP12 Inflammasome Recognizes Yersinia pestis. Immunity. 2012;37:96–107. doi: 10.1016/j.immuni.2012.07.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Williams GS, Malin M, Vremec D, Chang CH, Boyd R, Benoist C, Mathis D. Mice lacking the transcription factor CIITA—a second look. Int Immunol. 1998;10:1957–1967. doi: 10.1093/intimm/10.12.1957. [DOI] [PubMed] [Google Scholar]
- Williams KL, Taxman DJ, Linhoff MW, Reed W, Ting JPY. 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. 2003;170:5354–5358. doi: 10.4049/jimmunol.170.11.5354. [DOI] [PubMed] [Google Scholar]
- Yao Y, Wang Y, Chen F, Huang Y, Zhu S, Leng Q, Wang H, Shi Y, Qian Y. NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens. Cell Res. 2012;22:836–847. doi: 10.1038/cr.2012.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zaki MH, Vogel P, Malireddi RK, Body-Malapel M, Anand PK, Bertin J, Green DR, Lamkanfi M, Kanneganti TD. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell. 2011;20:649–660. doi: 10.1016/j.ccr.2011.10.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhao Y, Shao F. NLRC5: a NOD-like receptor protein with many faces in immune regulation. Cell Res. 2012;22:1099–1101. doi: 10.1038/cr.2012.83. [DOI] [PMC free article] [PubMed] [Google Scholar]