NOD‐Like Receptors


NOD‐like receptors (NLRs) are a family of pattern recognition receptors (PRRs), able to respond to conserved microbial structures and endogenous danger signals. NLRs modulate the inflammatory response via multiple pathways including NFκB (nuclear factor kappa‐light chain‐enhancer of activated B cells)‐activation, MAPKs, ERK and inflammasome formation, which results in IL‐1β release. They act in synergy with other PRRs, bridging innate to adaptive immunity. Moreover, some NLRs directly modulate adaptive immunity via transcriptional regulation of MHC (major histocompatibility complex) class I and class II. Their essential role in orchestrating inflammatory responses is seen via their association with morbidity. NLR dysfunction can result in cancer and autoinflammatory diseases, such as Crohn's disease and ulcerative colitis, pointing out their important role in maintaining gut homeostasis.

Key Concepts

  • NLRs are an intracellular subclass of PRRs that recognise microbe‐associated molecular patterns (MAMPs) and danger‐associated molecular patterns (DAMPs).
  • NLRs are found in different animal species and have homologues in plants.
  • NLRs share a common tripartite structure, typically consisting of an N‐terminal domain from the death‐fold family, a central NACHT domain and a variable number of C‐terminal LRRs.
  • Activation of NLRs primes innate and adaptive immunity and drives the expression of MHC class I and class II genes.
  • Some NLRs form inflammasomes, multiprotein platforms for caspase‐1 activation and IL‐1β release.
  • NLRs maintain gut homeostasis, differentiating between commensals and pathogens.
  • Mutations in NLRs can lead to severe autoinflammatory diseases, cancer, dysregulation of gut homeostasis and innate immune responses.
  • Evidence suggests that some NLRs are further implicated in development.
  • The function of some of the 22 human NLR proteins remains elusive.

Keywords: pattern recognition receptor (PRR); NOD‐like receptor (NLR); inflammasome; development; gut homeostasis; major histocompatibility complex (MHC); NODosome; innate immunity; NFκB; IL‐1β

Figure 1. Structure of NLRs. NLRs share a central NACHT (oligomerisation module, present in NAIP, CIITA, HET‐E, TP‐1) domain, a variable number of C‐terminal LRRs (leucine‐rich repeats) and a variable N‐terminal domain: a BIR (baculovirus IAP [inhibitor of apoptosis] repeat) domain, one or two CARD (caspase‐activating and recruitment domain), a CARD‐AD (CARD‐transcriptional activation domain) or a PYD (pyrin domain). The central NACHT domain harbours the Walker A and B motif, followed by a NACHT‐associated domain (NAD), containing for example the winged‐helix motif. NLRs have variable numbers of C‐terminal LRR, ranging from none (NLRP10) up to 27 (NLRC5).
Figure 2. NLRs as pattern recognition receptors. NLRs function as pattern recognition receptors in inflammatory response and gut homeostasis. NLR proteins are able to sense a variety of MAMP and DAMP signals (such as crystalline structures, MDP, iE‐DAP or commensal MAMPs) that converge and initiate the formation of either the NODosome or inflammasome and subsequent downstream inflammatory responses. Upon the correct physiological response, this results in pathogenic bacterial clearance, maintenance of commensal bacteria, mucin release and restored homeostasis. Upon dysfunction, it can lead to defective formation of intestinal lymphoid follicles, various autoinflammatory diseases and gut disturbances such as colitis and Crohn's disease. AMP, antimicrobial peptide; ATG16L1, autophagy molecule autophagy related 16‐like protein; ATP, adenosine triphosphate; DAMP, danger‐associated molecular patterns; iE‐DAP, y‐d‐glutamyl‐meso‐diaminopimelic acid; IL‐18, interleukin‐18; IL‐1β, interleukin‐1 beta; MAMP, microbe‐associated molecular patterns; MAPK, mitogen‐activated protein kinase; MAVS, mitochondrial antiviral signalling protein; MDP, muramyl dipeptide; NFκB, nuclear factor kappa‐light chain‐enhancer of activated B cells; OMV, outer membrane vesicles; RIPK2, receptor‐interacting serine/threonine‐protein kinase‐2; ROS, reactive oxygen species; T3SS, type‐III secretion system; TLR, toll‐like receptor
Figure 3. NLRs as transcriptional regulators. Transcriptional regulation by CIITA and NLRC5: IFNγ‐induced signal transducer and activator of transcription 1 (STAT1) mediates the transcription of CIITA and NLRC5. Both proteins shuttle into the nucleus and induce transcription of MHC class I and class II genes, respectively. MHC class I is loaded with antigens derived from endogenous proteins and intracellular pathogens in the ER and presents them to CD8+ T cells. MHC class II molecule binding site is blocked by an invariant chain (li) and is transported to the late endosome, where the li peptide is exchanged with antigens derived from exogenous antigens and presents them to CD4+ T cells. CD4+, CD4 positive T cell; CD8+, CD8 positive T cell; CIITA, MHC class II transcativator; IFNγ, interferon gamma; li, class II‐associated invariant chain peptide; MHC, major histocompatibility complex; NLRC, NLR family CARD domain‐containing protein; NLR, NOD‐like receptor; STAT1, signal transducer and activator of transcription 1
Figure 4. NLRs in development. NLRP5 and NLRP14 in development: NLRP14 inhibits the RIG‐I and cGAS‐mediated innate immune response against cytosolic nucleic acids during oocyte fertilisation. * symbolises the five known SNPs in NLRP14, which cause spermatogenetic failure and infertility. NLRP5 is part of a subcortical maternal complex that is essential for development of the zygote. NLRP, NACHT, LRR and PYD domain‐containing protein; SNP, single‐nucleotide polymorphism.


Abbott DW, Wilkins A, Asara JM, et al. (2004) The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Current Biology 14 (24): 2217–2227.

Abdul‐Sater AA, Said‐Sadier N, Lam VM, et al. (2010) Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial NOD‐like family member NLRX1. Journal of Biological Chemistry 285 (53): 41637–41645.

Abe T, Lee A, Sitharam R, et al. (2017) Germ‐cell‐specific inflammasome component NLRP14 negatively regulates cytosolic nucleic acid sensing to promote fertilization. Immunity 46 (4): 621–634.

Akira S and Takeda K (2004) Toll‐like receptor signalling. Nature Reviews. Immunology 4 (7): 499–511.

Allen IC, Tekippe EM, Woodford RM, et al. (2010) The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis‐associated cancer. Journal of Experimental Medicine 207 (5): 1045–1056.

Allen IC, Moore CB, Schneider M, et al. (2011) NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG‐I‐MAVS and TRAF6‐NF‐κB signaling pathways. Immunity 34 (6): 854–865.

Allen IC, Wilson JE, Schneider M, et al. (2012) NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF‐kappaB signaling. Immunity 36 (5): 742–754.

Anand PK, Malireddi RK, Lukens JR, et al. (2012) NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488 (7411): 389–393.

Arnoult D, Soares F, Tattoli I, et al. (2009) An N‐terminal addressing sequence targets NLRX1 to the mitochondrial matrix. Journal of Cell Science 122 (Pt 17): 3161–3168.

Ayabe T, Satchell DP, Wilson CL, et al. (2000) Secretion of microbicidal alpha‐defensins by intestinal paneth cells in response to bacteria. Nature Immunology 1 (2): 113–118.

Barber GN (2015) Sting: infection, inflammation and cancer. Nature Reviews. Immunology 15 (12): 760–770.

Barnich N, Aguirre JE, Reinecker HC, et al. (2005) Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor–κB activation in muramyl dipeptide recognition. Journal of Cell Biology 170 (1): 21–26.

Bauernfeind F, Niepmann S, Knolle PA, et al. (2016) Aging‐associated TNF production primes inflammasome activation and NLRP3‐related metabolic disturbances. Journal of Immunology 197 (7): 2900–2908.

Bebbere D, Masala L, Albertini DF, et al. (2016) The subcortical maternal complex: multiple functions for one biological structure? Journal of Assisted Reproduction and Genetics 33 (11): 1431–1438.

Behr MA and Divangahi M (2015) Freund's adjuvant, NOD2 and mycobacteria. Current Opinion in Microbiology 23: 126–132.

Belkaid Y and Harrison OJ (2017) Homeostatic immunity and the microbiota. Immunity 46 (4): 562–576.

Benko S, Magalhaes JG, Philpott DJ, et al. (2010) NLRC5 limits the activation of inflammatory pathways. Journal of Immunology 185 (3): 1681–1691.

Benk S, Kovács EG, Hezel F, et al. (2017) NLRC5 functions beyond MHC I regulation‐what do we know so far? Frontiers in Immunology 8: 150.

Benoist C and Mathis D (1990) Regulation of major histocompatibility complex class‐Ii genes: X, Y and other letters of the alphabet. Annual Review of Immunology 8: 681–715.

Bertrand MJ, Doiron K, Labbe K, et al. (2009) Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30 (6): 789–801.

Bielig H, Lautz K, Braun PR, et al. (2014) The cofilin phosphatase slingshot homolog 1 (SSH1) links NOD1 signaling to actin remodeling. PLoS Pathogens 10 (9): e1004351.

Bouskra D, Brezillon C, Berard M, et al. (2008) Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456 (7221): 507–510.

Broderick L, De Nardo D, Franklin BS, et al. (2015) The inflammasomes and autoinflammatory syndromes. Annual Review of Pathology 10: 395–424.

Bruey JM, Bruey‐Sedano N, Newman R, et al. (2004) PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF‐kappaB and caspase‐1 activation in macrophages. Journal of Biological Chemistry 279 (50): 51897–51907.

Burberry A, Zeng MY, Ding L, et al. (2014) Infection mobilizes hematopoietic stem cells through cooperative NOD‐like receptor and toll‐like receptor signaling. Cell Host & Microbe 15 (6): 779–791.

Carlström M, Ekman AK, Petersson S, et al. (2012) Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility. Experimental Dermatology 21 (12): 932–937.

Cavalli G and Dinarello CA (2015) Treating rheumatological diseases and co‐morbidities with interleukin‐1 blocking therapies. Rheumatology (Oxford) 54 (12): 2134–2144.

Chamaillard M, Hashimoto M, Horie Y, et al. (2003a) An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nature Immunology 4 (7): 702–707.

Chamaillard M, Philpott D, Girardin SE, et al. (2003b) Gene‐environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proceedings of the National Academy of Sciences of the United States of America 100 (6): 3455–3460.

Chang CH, Guerder S, Hong SC, et al. (1996) Mice lacking the MHC class II transactivator (CIITA) show tissue‐specific impairment of MHC class II expression. Immunity 4 (2): 167–178.

Chen GY, Liu M, Wang F, et al. (2011) A functional role for NLRP6 in intestinal inflammation and tumorigenesis. Journal of Immunology 186 (12): 7187–7194.

Chen L, Wilson JE, Koenigsknecht MJ, et al. (2017) NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nature Immunology 18 (5): 541–551.

Chin KC, Li GG and Ting JP (1997) Importance of acidic, proline/serine/threonine‐rich, and GTP‐binding regions in the major histocompatibility complex class II transactivator: generation of transdominant‐negative mutants. Proceedings of the National Academy of Sciences of the United States of America 94 (6): 2501–2506.

Clarke TB, Davis KM, Lysenko ES, et al. (2010) Recognition of peptidoglycan from the microbiota by NOD1 enhances systemic innate immunity. Nature Medicine 16 (2): 228–231.

Conti BJ, Davis BK, Zhang J, et al. (2005) Caterpiller 16.2 (CLR16.2), a novel NBD/LRR family member that negatively regulates T cell function. Journal of Biological Chemistry 280 (18): 18375–18385.

Cooney R, Baker J, Brain O, et al. (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nature Medicine 16 (1): 90–97.

Cui J, Zhu L, Xia X, et al. (2010) NLRC5 negatively regulates the NF‐kappaB and type I interferon signaling pathways. Cell 141 (3): 483–496.

Cui J, Li Y, Zhu L, et al. (2012) NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4. Nature Immunology 13 (4): 387–395.

Da Silva Correia J, Miranda Y, Austin‐Brown N, et al. (2006) NOD1‐dependent control of tumor growth. Proceedings of the National Academy of Sciences of the United States of America 103 (6): 1840–1845.

Damgaard RB, Nachbur U, Yabal M, et al. (2012) The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Molecular Cell 46 (6): 746–758.

Damm A, Giebeler N, Zamek J, et al. (2016) Epidermal NLRP10 contributes to contact hypersensitivity responses in mice. European Journal of Immunology 46 (8): 1959–1969.

Dangl JL and Jones JD (2001) Plant pathogens and integrated defence responses to infection. Nature 411 (6839): 826–833.

Danot O, Marquenet E, Vidal‐Ingigliardi D, et al. (2009) Wheel of life, wheel of death: a mechanistic insight into signaling by stand proteins. Structure 17 (2): 172–182.

Davis BK, Wen H and Ting JP (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annual Review of Immunology 29: 707–735.

De Jong HK, Koh G, Van Lieshout MHP, et al. (2014) Limited role for ASC and NLRP3 during in vivo Salmonella typhimurium infection. BMC Immunology 15: 30.

Duewell P, Kono H, Rayner KJ, et al. (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464 (7293): 1357–1361.

Dugan JW, Albor A, David L, et al. (2009) Nucleotide oligomerization domain‐2 interacts with 2′‐5′‐oligoadenylate synthetase type 2 and enhances RNase‐L function in THP‐1 cells. Molecular Immunology 47 (2–3): 560–566.

Eisenbarth SC, Williams A, Colegio OR, et al. (2012) NLRP10 is a NOD‐like receptor essential to initiate adaptive immunity by dendritic cells. Nature 484 (7395): 510–513.

Elinav E, Strowig T, Kau AL, et al. (2011) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145 (5): 745–757.

Faustin B, Lartigue L, Bruey JM, et al. (2007) Reconstituted NALP1 inflammasome reveals two‐step mechanism of caspase‐1 activation. Molecular Cell 25 (5): 713–724.

Fiorentino L, Stehlik C, Oliveira V, et al. (2002) A novel PAAD‐containing protein that modulates NF‐kappaB induction by cytokines tumor necrosis factor‐alpha and interleukin‐1beta. Journal of Biological Chemistry 277 (38): 35333–35340.

Flor HH (1971) Current status of the gene‐for‐gene concept. Annual Review of Phytopathology 9: 275–296.

Franchi L, Amer A, Body‐Malapel M, et al. (2006) Cytosolic flagellin requires Ipaf for activation of caspase‐1 and interleukin 1beta in salmonella‐infected macrophages. Nature Immunology 7 (6): 576–582.

Girardin SE, Tournebize R, Mavris M, et al. (2001) CARD4/NOD1 mediates NF‐kappaB and JNK activation by invasive Shigella flexneri. EMBO Reports 2 (8): 736–742.

Girardin SE, Boneca IG, Carneiro LA, et al. (2003a) NOD1 detects a unique muropeptide from gram‐negative bacterial peptidoglycan. Science 300 (5625): 1584–1587.

Girardin SE, Boneca IG, Viala J, et al. (2003b) NOD2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. Journal of Biological Chemistry 278 (11): 8869–8872.

Girardin SE, Jehanno M, Mengin‐Lecreulx D, et al. (2005) Identification of the critical residues involved in peptidoglycan detection by NOD1. Journal of Biological Chemistry 280 (46): 38648–38656.

Grenier JM, Wang L, Manji GA, et al. (2002) Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF‐kappaB and caspase‐1. FEBS Letters 530 (1–3): 73–78.

Gutte PG, Jurt S, Grütter MG, et al. (2014) Unusual structural features revealed by the solution NMR structure of the NLRC5 caspase recruitment domain. Biochemistry 53 (19): 3106–3117.

Hake SB, Masternak K, Kammerbauer C, et al. (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. Molecular and Cellular Biology 20 (20): 7716–7725.

Hamatani T, Falco G, Carter MG, et al. (2004) Age‐associated alteration of gene expression patterns in mouse oocytes. Human Molecular Genetics 13 (19): 2263–2278.

Haneklaus M and O'neill LA (2015) NLRP3 at the interface of metabolism and inflammation. Immunological Reviews 265 (1): 53–62.

Harton JA, Cressman DE, Chin KC, et al. (1999) GTP binding by class II transactivator: role in nuclear import. Science 285 (5432): 1402–1405.

Hasegawa M, Fujimoto Y, Lucas PC, et al. (2008) A critical role of RICK/RIP2 polyubiquitination in NOD‐induced NF‐kappaB activation. EMBO Journal 27 (2): 373–383.

Henao‐Mejia J, Elinav E, Jin C, et al. (2012) Inflammasome‐mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482 (7384): 179–185.

Hirota T, Nakayama T, Sato S, et al. (2017) Association study of childhood food allergy with GWAS‐discovered loci of atopic dermatitis and eosinophilic esophagitis. Journal of Allergy and Clinical Immunology. in press.

Hoffman HM and Wanderer AA (2010) Inflammasome and Il‐1beta‐mediated disorders. Current Allergy and Asthma Reports 10 (4): 229–235.

Homer CR, Richmond AL, Rebert NA, et al. (2010) Atg16l1 and NOD2 interact in an autophagy‐dependent antibacterial pathway implicated in Crohn's disease pathogenesis. Gastroenterology 139 (5): 1630–1641, 1641.e1631–1632.

Hong M, Yoon SI and Wilson IA (2012) Structure and functional characterization of the RNA‐binding element of the NLRX1 innate immune modulator. Immunity 36 (3): 337–347.

Hu Z, Yan C, Liu P, et al. (2013) Crystal structure of NLRC4 reveals its autoinhibition mechanism. Science 341 (6142): 172–175.

Hugot JP, Chamaillard M, Zouali H, et al. (2001) Association of NOD2 leucine‐rich repeat variants with susceptibility to Crohn's disease. Nature 411 (6837): 599–603.

Hysi P, Kabesch M, Moffatt MF, et al. (2005) NOD1 variation, immunoglobulin E and asthma. Human Molecular Genetics 14 (7): 935–941.

Ikeda F, Deribe YL, Skanland SS, et al. (2011) SHARPIN forms a linear ubiquitin ligase complex regulating NF‐kappaB activity and apoptosis. Nature 471 (7340): 637–641.

Inohara N, Koseki T, Lin J, et al. (2000) An induced proximity model for NF‐kappaB activation in the NOD1/RICK and RIP signaling pathways. Journal of Biological Chemistry 275 (36): 27823–27831.

Inohara N, Ogura Y, Fontalba A, et al. (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. Journal of Biological Chemistry 278 (8): 5509–5512.

Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harbor Symposia on Quantitative Biology 54 (Pt 1): 1–13.

Jaworska J, Coulombe F, Downey J, et al. (2014) NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1‐F2 protein. Proceedings of the National Academy of Sciences of the United States of America 111 (20): E2110–E2119.

Jéru I, Duquesnoy P, Fernandes‐Alnemri T, et al. (2008) Mutations in NALP12 cause hereditary periodic fever syndromes. Proceedings of the National Academy of Sciences of the United States of America 105 (5): 1614–1619.

Jin Y, Mailloux CM, Gowan K, et al. (2007) NALP1 in vitiligo‐associated multiple autoimmune disease. New England Journal of Medicine 356 (12): 1216–1225.

Jones JD, Vance RE and Dangl JL (2016) Intracellular innate immune surveillance devices in plants and animals. Science 354 (6316): pii: aaf6395.

Kanneganti TD, Ozoren N, Body‐Malapel M, et al. (2006) Bacterial RNA and small antiviral compounds activate caspase‐1 through cryopyrin/Nalp3. Nature 440 (7081): 233–236.

Kaparakis M, Turnbull L, Carneiro L, et al. (2010) Bacterial membrane vesicles deliver peptidoglycan to NOD1 in epithelial cells. Cellular Microbiology 12 (3): 372–385.

Karki R, Man SM, Malireddi RK, et al. (2016) NLRC3 is an inhibitory sensor of PI3K‐mTOR pathways in cancer. Nature 540: 583–587.

Keestra AM, Winter MG, Auburger JJ, et al. (2013) Manipulation of small Rho GTPases is a pathogen‐induced process detected by NOD1. Nature 496 (7444): 233–237.

Kim YK, Shin JS and Nahm MH (2016) NOD‐like receptors in infection, immunity, and diseases. Yonsei Medical Journal 57 (1): 5–14.

Kinoshita T, Wang Y, Hasegawa M, et al. (2005) PYPAF3, a pyrin‐containing APAF‐1‐like protein, is a feedback regulator of caspase‐1‐dependent interleukin‐1beta secretion. Journal of Biological Chemistry 280 (23): 21720–21725.

Kong X, Yuan Z and Cheng J (2017) The function of NOD‐like receptors in central nervous system diseases. Journal of Neuroscience Research 95 (8): 1565–1573.

Krieg A, Correa RG, Garrison JB, et al. (2009) XIAP mediates NOD signaling via interaction with RIP2. Proceedings of the National Academy of Sciences of the United States of America 106 (34): 14524–14529.

Kuchmiy AA, D'hont J, Hochepied T, et al. (2016) NLRP2 controls age‐associated maternal fertility. Journal of Experimental Medicine 213 (13): 2851–2860.

Kuenzel S, Till A, Winkler M, et al. (2010) The nucleotide‐binding oligomerization domain‐like receptor NLRC5 is involved in IFN‐dependent antiviral immune responses. Journal of Immunology 184 (4): 1990–2000.

Kufer TA, Kremmer E, Banks DJ, et al. (2006) Role for Erbin in bacterial activation of NOD2. Infection and Immunity 74 (6): 3115–3124.

Kufer TA and Sansonetti PJ (2007) Sensing of bacteria: NOD a lonely Job. Current Opinion in Microbiology 10 (1): 62–69.

Kufer TA, Kremmer E, Adam AC, et al. (2008) The pattern‐recognition molecule NOD1 is localized at the plasma membrane at sites of bacterial interaction. Cellular Microbiology 10 (2): 477–486.

Lautz K, Damm A, Menning M, et al. (2012) NLRP10 enhances Shigella‐induced pro‐inflammatory responses. Cellular Microbiology 14 (10): 1568–1583.

Lecine P, Esmiol S, Metais JY, et al. (2007) The NOD2‐RICK complex signals from the plasma membrane. Journal of Biological Chemistry 282 (20): 15197–15207.

Leipe DD, Koonin EV and Aravind L (2004) STAND, a class of P‐loop NTPases including animal and plant regulators of programmed cell death: multiple, complex domain architectures, unusual phyletic patterns, and evolution by horizontal gene transfer. Journal of Molecular Biology 343 (1): 1–28.

Li L, Baibakov B and Dean J (2008) A subcortical maternal complex essential for preimplantation mouse embryogenesis. Developmental Cell 15 (3): 416–425.

Lin C and Zhang J (2017) Inflammasomes in inflammation‐induced cancer. Frontiers in Immunology 8: 271.

Lipinski S, Grabe N, Jacobs G, et al. (2012) RNAi screening identifies mediators of NOD2 signaling: implications for spatial specificity of MDP recognition. Proceedings of the National Academy of Sciences of the United States of America 109 (52): 21426–21431.

Loo YM and Gale M (2011) Immune signaling by RIG‐I‐like receptors. Immunity 34 (5): 680–692.

Ludigs K, Seguin‐Estevez Q, Lemeille S, et al. (2015) NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module. PLoS Genetics 11 (3): e1005088.

Ludigs K, Jandus C, Utzschneider DT, et al. (2016) NLRC5 shields T lymphocytes from NK‐cell‐mediated elimination under inflammatory conditions. Nature Communications 7: 10554.

Lupfer CR, Stokes KL, Kuriakose T, et al. (2017) Deficiency of the NOD‐like receptor NLRC5 results in decreased Cd8(+) T cell function and impaired viral clearance. Journal of Virology 91 (17): pii: e00377–17.

Macaluso F, Nothnagel M, Parwez Q, et al. (2007) Polymorphisms in NACHT‐LRR (NLR) genes in atopic dermatitis. Experimental Dermatology 16 (8): 692–698.

Magalhaes JG, Philpott DJ, Nahori MA, et al. (2005) Murine NOD1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin. EMBO Reports 6 (12): 1201–1207.

Magitta NF, Boe Wolff AS, Johansson S, et al. (2009) A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes. Genes and Immunity 10 (2): 120–124.

Mamantopoulos M, Ronchi F, Van Hauwermeiren F, et al. (2017) Nlrp6‐ and ASC‐dependent inflammasomes do not shape the commensal gut microbiota composition. Immunity 47 (2): 339–348.

Man SM, Hopkins LJ, Nugent E, et al. (2014) Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex. Proceedings of the National Academy of Sciences of the United States of America 111 (20): 7403–7408.

Mariathasan S, Weiss DS, Newton K, et al. (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440 (7081): 228–232.

Matzinger P (1994) Tolerance, danger, and the extended family. Annual Review of Immunology 12: 991–1045.

Mayor A, Martinon F, De Smedt T, et al. (2007) A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nature Immunology 8 (5): 497–503.

Mcdonald C, Chen FF, Ollendorff V, et al. (2005) A role for Erbin in the regulation of NOD2‐dependent NF‐kappaB signaling. Journal of Biological Chemistry 280 (48): 40301–40309.

Meissner TB, Li A, Biswas A, et al. (2010) NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proceedings of the National Academy of Sciences of the United States of America 107 (31): 13794–13799.

Meissner TB, Li A and Kobayashi KS (2012a) NLRC5: a newly discovered MHC class I transactivator (CITA). Microbes and Infection 14 (6): 477–484.

Meissner TB, Liu YJ, Lee KH, et al. (2012b) NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. Journal of Immunology 188 (10): 4951–4958.

Meyer E, Lim D, Pasha S, et al. (2009) Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith‐Wiedemann Syndrome). PLoS Genetics 5 (3): e1000423.

Miao EA, Leaf IA, Treuting PM, et al. (2010) Caspase‐1‐induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nature Immunology 11 (12): 1136–1142.

Miceli‐Richard C, Lesage S, Rybojad M, et al. (2001) CARD15 mutations in Blau syndrome. Nature Genetics 29 (1): 19–20.

Minkiewicz J, De Rivero Vaccari JP and Keane RW (2013) Human astrocytes express a novel NLRP2 inflammasome. Glia 61 (7): 1113–1121.

Mo J, Boyle JP, Howard CB, et al. (2012) Pathogen sensing by nucleotide‐binding oligomerization domain‐containing protein 2 (NOD2) is mediated by direct binding to muramyl dipeptide and ATP. Journal of Biological Chemistry 287 (27): 23057–23067.

Moore CB, Bergstralh DT, Duncan JA, et al. (2008) NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451 (7178): 573–577.

Motta V, Soares F, Sun T, et al. (2015) NOD‐like receptors: versatile cytosolic sentinels. Physiological Reviews 95 (1): 149–178.

Muhlethaler‐Mottet A, Otten LA, Steimle V, et al. (1997) 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 Journal 16 (10): 2851–2860.

Murdoch S, Djuric U, Mazhar B, et al. (2006) Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nature Genetics 38 (3): 300–302.

Neerincx A, Lautz K, Menning M, et al. (2010) A role for the human nucleotide‐binding domain, leucine‐rich repeat‐containing family member NLRC5 in antiviral responses. Journal of Biological Chemistry 285 (34): 26223–26232.

Neerincx A, Rodriguez GM, Steimle V, et al. (2012) NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome‐dependent manner. Journal of Immunology 188 (10): 4940–4950.

Neerincx A, Jakobshagen K, Utermöhlen O, et al. (2014) The N‐terminal domain of NLRC5 confers transcriptional activity for MHC class I and II gene expression. Journal of Immunology 193 (6): 3090–3100.

Netea MG, Balkwill F, Chonchol M, et al. (2017) A guiding Map for inflammation. Nature Immunology 18 (8): 826–831.

Normand S, Delanoye‐Crespin A, Bressenot A, et al. (2011) NOD‐like receptor pyrin domain‐containing protein 6 (NLRP6) controls epithelial self‐renewal and colorectal carcinogenesis upon injury. Proceedings of the National Academy of Sciences of the United States of America 108 (23): 9601–9606.

Ogura Y, Bonen DK, Inohara N, et al. (2001a) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411 (6837): 603–606.

Ogura Y, Inohara N, Benito A, et al. (2001b) NOD2, a NOD1/APAF‐1 family member that is restricted to monocytes and activates NF‐kappaB. Journal of Biological Chemistry 276 (7): 4812–4818.

Ogura Y, Lala S, Xin W, et al. (2003) Expression of NOD2 in paneth cells: a possible link to Crohn's ileitis. Gut 52 (11): 1591–1597.

Pan Q, Kravchenko V, Katz A, et al. (2006) NF‐kappa B‐inducing kinase regulates selected gene expression in the NOD2 signaling pathway. Infection and Immunity 74 (4): 2121–2127.

Park JH, Kim YG, Mcdonald C, et al. (2007) RICK/RIP2 mediates innate immune responses induced through NOD1 and NOD2 but not TLRs. Journal of Immunology 178 (4): 2380–2386.

Parlato M and Yeretssian G (2014) NOD‐like receptors in intestinal homeostasis and epithelial tissue repair. International Journal of Molecular Sciences 15 (6): 9594–9627.

Peng H, Chang B, Lu C, et al. (2012) NLRP2, a maternal effect gene required for early embryonic development in the mouse. PLoS One 7 (1): e30344.

Philpott DJ, Girardin SE and Sansonetti PJ (2001) Innate immune responses of epithelial cells following infection with bacterial pathogens. Current Opinion in Immunology 13 (4): 410–416.

Pontillo A, Brandao L, Guimaraes R, et al. (2010) Two SNPs in NLRP3 gene are involved in the predisposition to type‐1 diabetes and celiac disease in a pediatric population from northeast Brazil. Autoimmunity 43 (8): 583–589.

Pontillo A, Catamo E, Arosio B, et al. (2012a) NALP1/NLRP1 genetic variants are associated with Alzheimer disease. Alzheimer Disease & Associated Disorders 26 (3): 277–281.

Pontillo A, Girardelli M, Kamada AJ, et al. (2012b) Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity 45 (4): 271–278.

Pontillo A, Bricher P, Leal VN, et al. (2016) Role of inflammasome genetics in susceptibility to HPV infection and cervical cancer development. Journal of Medical Virology 88 (9): 1646–1651.

Proell M, Riedl SJ, Fritz JH, et al. (2008) The NOD‐like receptor (NLR) family: a tale of similarities and differences. PLoS One 3 (4): e2119.

Rauch I, Deets KA, Ji DX, et al. (2017) NAIP‐NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and IL‐18 release via activation of caspase‐1 and ‐8. Immunity 46 (4): 649–659.

Raval A, Weissman JD, Howcroft TK, et al. (2003) The GTP‐binding domain of class II transactivator regulates its nuclear export. Journal of Immunology 170 (2): 922–930.

Rebsamen M, Vazquez J, Tardivel A, et al. (2011) NLRX1/NOD5 deficiency does not affect MAVS signalling. Cell Death and Differentiation 18 (8): 1387.

Robbins GR, Truax AD, Davis BK, et al. (2012) Regulation of class I major histocompatibility complex (MHC) by nucleotide‐binding domain, leucine‐rich repeat‐containing (NLR) proteins. Journal of Biological Chemistry 287 (29): 24294–24303.

Rosenstiel P, Huse K, Till A, et al. (2006) A short isoform of NOD2/CARD15, NOD2‐S, is an endogenous inhibitor of NOD2/receptor‐interacting protein kinase 2‐induced signaling pathways. Proceedings of the National Academy of Sciences of the United States of America 103 (9): 3280–3285.

Rosenstiel P, Till A and Schreiber S (2007) NOD‐like receptors and human diseases. Microbes and Infection 9 (5): 648–657.

Roy N, Mahadevan MS, Mclean M, et al. (1995) The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80 (1): 167–178.

Sabbah A, Chang TH, Harnack R, et al. (2009) Activation of innate immune antiviral response by NOD2. Nature Immunology 10 (10): 1073–1080.

Salcedo R, Worschech A, Cardone M, et al. (2010) MyD88‐mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. Journal of Experimental Medicine 207 (8): 1625–1636.

Schneider M, Zimmermann AG, Roberts RA, 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. Nature Immunology 13 (9): 823–831.

Schooten E, Klous P, Van Den Elsen PJ, et al. (2005) Lack of MHC‐Ii expression in activated mouse T cells correlates with DNA methylation at the CIITA‐PIII region. Immunogenetics 57 (10): 795–799.

Schroder K and Tschopp J (2010) The inflammasomes. Cell 140 (6): 821–832.

Sharma D and Kanneganti TD (2016) The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. Journal of Cell Biology 213 (6): 617–629.

Sharma N and Jha S (2016) NLR‐regulated pathways in cancer: opportunities and obstacles for therapeutic interventions. Cellular and Molecular Life Sciences 73 (9): 1741–1764.

Soares F, Tattoli I, Wortzman ME, et al. (2013) NLRX1 does Not inhibit MAVS‐dependent antiviral signalling. Innate Immunity 19 (4): 438–448.

Staehli F, Ludigs K, Heinz LX, et al. (2012) NLRC5 deficiency selectively impairs MHC class I‐ dependent lymphocyte killing by cytotoxic T cells. Journal of Immunology 188 (8): 3820–3828.

Steidl C, Shah SP, Woolcock BW, et al. (2011) MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471 (7338): 377–381.

Steimle V, Otten LA, Zufferey M, et al. (1993) Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 75 (1): 135–146.

Stenzel N, Fetzer CP, Heumann R, et al. (2009) PDZ‐domain‐directed basolateral targeting of the peripheral membrane protein FRMPD2 in epithelial cells. Journal of Cell Science 122 (Pt 18): 3374–3384.

Sui J, Li H, Fang Y, et al. (2012) NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in Han Chinese. Arthritis and Rheumatism 64 (3): 647–654.

Sutterwala FS, Ogura Y, Szczepanik M, et al. (2006) Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase‐1. Immunity 24 (3): 317–327.

Tanabe T, Chamaillard M, Ogura Y, et al. (2004) Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO Journal 23 (7): 1587–1597.

Tao M, Scacheri PC, Marinis JM, et al. (2009) ITCH K63‐ubiquitinates the NOD2 binding protein, RIP2, to influence inflammatory signaling pathways. Current Biology 19 (15): 1255–1263.

Tattoli I, Carneiro LA, Jehanno M, et al. (2008) NLRX1 is a mitochondrial NOD‐like receptor that amplifies NF‐kappaB and JNK pathways by inducing reactive oxygen species production. EMBO Reports 9 (3): 293–300.

Tenthorey JL, Kofoed EM, Daugherty MD, et al. (2014) Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Molecular Cell 54 (1): 17–29.

Thay B, Damm A, Kufer TA, et al. (2014) Aggregatibacter actinomycetemcomitans outer membrane vesicles are internalized in human host cells and trigger NOD1‐ and NOD2‐dependent NF‐kappa B activation. Infection and Immunity 82 (10): 4034–4046.

Ting JP, Lovering RC, Alnemri ES, et al. (2008) The NLR gene family: a standard nomenclature. Immunity 28 (3): 285–287.

Tokunaga F, Nakagawa T, Nakahara M, et al. (2011) Sharpin is a component of the NF‐kappaB‐activating linear ubiquitin chain assembly complex. Nature 471 (7340): 633–636.

Tong ZB, Gold L, Pfeifer KE, et al. (2000) Mater, a maternal effect gene required for early embryonic development in mice. Nature Genetics 26 (3): 267–268.

Travassos LH, Carneiro LA, Ramjeet M, et al. (2010) NOD1 and NOD2 direct autophagy by recruiting ATG16l1 to the plasma membrane at the site of bacterial entry. Nature Immunology 11 (1): 55–62.

Van Den Elsen PJ, Holling TM, Kuipers HF, et al. (2004) Transcriptional regulation of antigen presentation. Current Opinion in Immunology 16 (1): 67–75.

Van Den Elsen PJ (2011) Expression regulation of major histocompatibility complex class I and class II encoding genes. Frontiers in Immunology 2: 48.

Von Kampen O, Lipinski S, Till A, et al. (2010) Caspase recruitment domain‐containing protein 8 (CARD8) negatively regulates NOD2‐mediated signaling. Journal of Biological Chemistry 285 (26): 19921–19926.

Wang Y, Hasegawa M, Imamura R, et al. (2004) PYNOD, a novel Apaf‐1/CED4‐like protein is an inhibitor of ASC and caspase‐1. International Immunology 16 (6): 777–786.

Westerveld GH, Korver CM, Van Pelt AM, et al. (2006) Mutations in the testis‐specific NALP14 gene in men suffering from spermatogenic failure. Human Reproduction 21 (12): 3178–3184.

Williams KL, Lich JD, Duncan JA, et al. (2005) The caterpiller protein monarch‐1 is an antagonist of toll‐like receptor‐, tumor necrosis factor alpha‐, and Mycobacterium tuberculosis‐induced pro‐inflammatory signals. Journal of Biological Chemistry 280 (48): 39914–39924.

Wlodarska M, Thaiss CA, Nowarski R, et al. (2014) NLRP6 inflammasome orchestrates the colonic host‐microbial interface by regulating goblet cell mucus secretion. Cell 156 (5): 1045–1059.

Wright KL and Ting JP (2006) Epigenetic regulation of MHC‐II and CIITA genes. Trends in Immunology 27 (9): 405–412.

Xia X, Cui J, Wang HY, et al. (2011) NLRX1 negatively regulates TLR‐induced NF‐kappaB signaling by targeting TRAF6 and IKK. Immunity 34 (6): 843–853.

Yamamoto M, Yaginuma K, Tsutsui H, et al. (2004) ASC is essential for LPS‐induced activation of procaspase‐1 independently of TLR‐associated signal adaptor molecules. Genes to Cells 9 (11): 1055–1067.

Ye Z, Lich JD, Moore CB, et al. (2008) ATP binding by monarch‐1/NLRP12 is critical for its inhibitory function. Molecular and Cellular Biology 28 (5): 1841–1850.

Yoshihama S, Vijayan S, Sidiq T, et al. (2017) NLRC5/CITA: a key player in cancer immune surveillance. Trends in Cancer 3 (1): 28–38.

Zaki MH, Boyd KL, Vogel P, et al. (2010) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32 (3): 379–391.

Zaki MH, Vogel P, Malireddi RK, et al. (2011) The NOD‐like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20 (5): 649–660.

Zhang P, Dixon M, Zucchelli M, et al. (2008) Expression analysis of the NLRP gene family suggests a role in human preimplantation development. PLoS One 3 (7): e2755.

Zhang L, Mo J, Swanson KV, et al. (2014) NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor sting. Immunity 40 (3): 329–341.

Zhao Y, Yang J, Shi J, et al. (2011) The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477 (7366): 596–600.

Zhao Q, Peng L, Huang W, et al. (2012) Rare inborn errors associated with chronic hepatitis B virus infection. Hepatology 56 (5): 1661–1670.

Zhao Y and Shao F (2015) The NAIP‐NLRC4 inflammasome in innate immune detection of bacterial flagellin and type III secretion apparatus. Immunological Reviews 265 (1): 85–102.

Zurawek M, Fichna M, Januszkiewicz‐Lewandowska D, et al. (2010) A coding variant in NLRP1 is associated with autoimmune Addison's disease. Human Immunology 71 (5): 530–534.

Further Reading

Belkaid Y and Harrison OJ (2017) Homeostatic immunity and the microbiota. Immunity 46 (4): 562–576.

Broz P and Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nature Reviews. Immunology 16 (7): 407–420.

Chelbi ST, Dang AT and Guarda G (2017) Emerging major histocompatibility complex class I‐related functions of NLRC5. Advances in Immunology 133: 89–119.

Garlanda C, Dinarello CA and Mantovani A (2013) The interleukin‐1 family: back to the future. Immunity 39 (6): 1003–1018.

Jesus AA and Goldbach‐Mansky R (2014) IL‐1 blockade in autoinflammatory syndromes. Annual Review of Medicine 65: 223–244.

Kufer TA and Fritz JH (2015) NLR‐Protein Functions in Immunity. Frontiers Media SAin Immunology 6: 306.

Meunier E and Broz P (2017) Evolutionary convergence and divergence in NLR function and structure. Trends in Immunology 38 (10): 744–757.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Arnold, Christine, Kienes, Ioannis, Sowa, Anna S, and Kufer, Thomas A(Jan 2018) NOD‐Like Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026236]