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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Immunity. Author manuscript; available in PMC 2009 March 1.
Published in final edited form as:
PMCID: PMC2630772

The NLR gene family: An official nomenclature

Jenny P.-Y. Ting
Jenny P.-Y. Ting, Lineberger Comprehensive Cancer Center Department of Microbiology-Immunology University of North Carolina Chapel Hill, NC, 27599, USA ; ude.cnu.dem@gnit_ynnej;
Ruth C. Lovering
Ruth C. Lovering, HUGO Gene Nomenclature Committee The Galton Laboratory University College London, NW1 2HE, UK ;;
Emad S. Ph.D. Alnemri
Emad S. Ph.D. Alnemri, Kimmel Cancer Institute Thomas Jefferson University Philadelphia, PA 19107, USA ; ude.ujt.icj.liam@irmenlae;
John Bertin
John Bertin, Synta Pharmaceuticals Lexington, MA 02421, USA ; moc.amrahpatnys@nitrebj;.
Jeremy M. Boss
Jeremy M. Boss, Department of Microbiology and Immunology Emory University School of Medicine Atlanta, GA 30322, USA ; ude.yrome.oiborcim@ssob;
Beckley Davis, Ph.D.
Beckley Davis, Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, NC, 27599, USA ; ude.cnu.dem@sivadp_yelkceb;
Richard A. Flavell, Ph.D., FRS
Richard A. Flavell, Department of Immunobiology Howard Hughes Medical Institute Yale University School of Medicine New Haven, CT 06520-8011, USA;
Stephen E. Girardin, PhD
Stephen E. Girardin, Dept of Laboratory Medicine & Pathobiology University of Toronto Toronto, Ontario M5S 1A8, Canada ; ac.otnorotu@nidrarig.nehpets;
Adam Godzik
Adam Godzik, The Burnham Institute La Jolla, CA 92037, USA ; gro.mahnrub@mada;
Jonathan A. Harton
Jonathan A. Harton, Ctr for Immunology & Microbial Disease Albany Medical College Albany, NY 12208, USA ; ude.cma.liam@jnotrah;.
Hal M Hoffman
Hal M Hoffman, University of California at San Diego Department of Pediatrics La Jolla, CA 92093-0635, USA ; ude.dscu@namffohah;
Jean-Pierre Hugot
Jean-Pierre Hugot, INSERM U843 Faculté de médecine Paris Diderot Hopital Robert Debré Paris, France. rf.phpa.bdr@toguh.erreip-naej;
Naohiro Inohara
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Department of Biochemistry II Interdisciplinary Graduate School of Medicine and Engineering University of Yamanashi Yamanashi 409-3898, Japan. ude.hcimu@oni
Alex MacKenzie
Alex MacKenzie, Children's Hospital of Eastern Ontario University of Ottawa Ottawa, Ontario Canada K1H 8L1 ;;
Lois J. Maltais
Lois J. Maltais, Mouse Genomic Nomenclature Committee The Jackson Laboratory, Bar Harbor, ME 0460, USA ; gro.xaj.scitamrofni@mjl;
Gabriel Nunez
Gabriel Nunez, Department of Pathology The University of Michigan Med School Ann Arbor, MI 48109, USA ; ude.hcimu@xlcb;
Yasunori Ogura
Yasunori Ogura, Yale University School of Medicine Section of Immunobiology New Haven, CT 06520-8011, USA ; ude.elay@arugo.ironusay;
Luc Otten
Luc Otten, Département de Biochimie Faculté de biologie et médecine Université de Lausanne Suisse ; hc.linu@nettO.cuL;
John C. Reed
John C. Reed, Burnham Institute for Medical Research La Jolla, CA 92037, USA ; gro.mahnrub@eciffodeer;
Walter Reith
Walter Reith, Department of Pathology and Immunology University of Geneva Medical School Geneva 4, Switzerland ; hc.eginu.enicedem@htieR.retlaW;
Stefan Schreiber
Stefan Schreiber, Institute for Clinical Molecular Biology Christian-Albrechts-University Kiel, Germany ; ed.asocum@rebierhcs.s;
Viktor Steimle
Viktor Steimle, Departement de Biologie Universite de Sherbrooke Sherbrooke, Quebec, J1K 2R1 Canada ; ac.ekoorbrehsu@elmietS.rotkiV;


Iimmune regulatory proteins such as CIITA, NAIP, IPAF, NOD1, NOD2, NALP1, cryopyrin/NALP3 are members of a family characterized by the presence of a nucleotide-binding domain (NBD) and leucine-rich repeats (LRR). Members of this gene family encode a protein structure similar to the NB-LRR subgroup of disease-resistance genes in plants and are involved in the sensing of pathogenic products and the regulation of cell signaling and apoptosis. Several members of this family have been associated with immunologic disorders. NOD2 for instance is associated with both Crohn's disease and Blau syndrome.

A variety of different names are currently used to describe this gene family, its subfamilies and individual genes, including CATERPILLER (CLR), NOD-LRR, NACHT-LRR, CARD, NALP, NOD, PAN and PYPAF, and this lack of consistency has led to a pressing need to unify the nomenclature. Consequently, we collectively propose the family designation NLR (nucleotide-binding domain and leucine-rich repeat containing) and provide unique and standardized gene designations for all family members.

The genomic mining of evolutionary conserved gene families with structural similarity and functional overlap has led to the discovery of important pathways in the immune system. This is highlighted by the discovery of a large gene family encoding proteins with a characteristic arrangement of a nucleotide binding domain (NBD) and leucine rich repeat (LRR) in both plants and animals. Plants lack an adaptive immune system and rely on two major disease resistance genetic systems for combating pathogens. One encodes the transmembrane pattern recognition receptors (PRRs) and the second encodes the nucleotide-binding, leucine rich repeat proteins (NB-LRR (Jones and Dangl, 2006)). In addition to the NB-LRR domains plant NB-LRR genes also encode one of two possible N-terminal domains, either a coiled-coil or a TIR (TLR-IL1/18 receptor). Most plant NB-LRR proteins act primarily through an intracellular route and appear to recognize pathogens indirectly, although direct recognition is also possible. The consequence of pathogen sensing is a hypersensitive cell death response resulting in the restriction of pathogen spreading.

In the early 2000s, an NB-LRR-related gene family (NLR) and subfamilies were discovered in humans and named by various groups as CATERPILLER (Harton et al., 2002; Ting and Davis, 2005), NODs (Inohara et al., 2002), NOD-LRR (Inohara et al., 2005; Inohara and Nunez, 2003), NACHT-LRR, (Martinon and Tschopp, 2005) and NOD-like receptor (Fritz et al., 2006; Meylan et al., 2006) (Table 1). It is now recognized that NLR genes are found in animal species ranging from sea urchin to human and are thought to function mainly in the innate immune response.

The nucleotide binding domain of the NLR gene family has characteristic features which led to the alternative name of NACHT. The name NACHT is derived from the four plant and animal proteins which initially defined the unique features of this domain: the neuronal apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomerase-associated protein (TP1) (Koonin and Aravind, 2000) In both plants and animals, the NACHT domain has NTPase activity and exhibits preferential binding for GTP or ATP. The majority of family members also contain a domain comprised of two to ten conserved motifs and often referred to as the NACHT-associated domain (NAD).

The NLR family includes several subfamilies distinguishable by their N-terminal effector domains. There are 4 recognizable NLR N-terminal domains: acidic transactivation, pyrin, caspase recruitment domain (CARD), and baculoviral inhibitory repeat (BIR)-like domains (Table 1). These N-terminal domains have been used by several groups to subdivide the NLR gene family and there are now multiple names for each subfamily: the pyrin-containing subfamily has been named PAN, PYPAF, and NALP (Grenier et al., 2002; Pawlowski et al., 2001; Tschopp et al., 2003); members of the CARD-containing subfamily have been named CARD (Bertin et al., 1999) or NODs (Inohara et al., 2002); the BIR-containing subfamily has been named NAIP or BIRC (Roy et al., 1995). The inconsistent use of these names has resulted in further complexity and potential confusion.

In consultation with over 100 scientists and the human and mouse Gene Nomenclature Committees, a new nomenclature system has been agreed upon (Table 1). It was agreed that the family name “Nucleotide-binding domain and leucine-rich repeat containing” (NLR) should be used to highlight these two evolutionary conserved domains and to reflect the similarity of the NLR family to the plant NB-LRR proteins.

A subfamily derived nomenclature system is provided for the NLR family based on the N-terminal effector domains (e.g. CARD, PYD and BIR, Table 1) or reflecting the more commonly used names for the well-published proteins CIITA, NAIP, NOD1 and NOD2. Human genes are written in upper case, whereas murine orthologs are distinguished from the human genes by the use of upper case for the first letter only, followed by lower case. Although several human NLR genes have multiple murine paralogs, some human NLR genes do not appear to have any murine counterparts, reflecting the dynamic evolutionary contraction and expansion of this family.

Existing data indicate several roles for these proteins in innate immunity. A prominent role is the recognition or “sensing” of pathogen products. The general strategy employed by most in the field is to demonstrate that the presence of a specific NLR protein is required for cellular responses to specific pathogen product(s). However the exact mechanism by which this recognition is achieved is not well understood and direct interaction between the NLR protein and microbial-derived product has not been demonstrated for any of these proteins. Nonetheless such an approach has been very useful in gauging the function of NLRs. NOD1 and NOD2 are revealed to mediate responses to the peptidoglycan-derived products meso-diamiopimelic acid and muramyl dipeptide respectively (Fritz et al., 2006). NLRP1 and NLRP3 mediate formation of the inflammasome complex required for caspase 1 maturation leading to the processing of pro-IL-1/IL-18 to mature IL-1/IL-18 in response to a host of pathogens and pathogen-derived products (Martinon and Tschopp, 2004, Ogura et al., 2006). These products include bacterial and viral-derived products as well as gout crystals and TLR3/7/8 agonists. NLRC4 and Naip5 are important for cellular responses to Salmonella and Legionella (Franchi et al., 2006; Mariathasan et al., 2004; Miao et al., 2006; Molofsky et al., 2006; Ren et al., 2006; Zamboni et al., 2006). Additionally, several of these proteins appear to mediate negative regulatory function in controlling pathologic inflammatory responses, including NLRC3, NLRP2, NLRP7 and NLRP12 (Bruey et al., 2004; Williams et al., 2005). More recent evidence indicates that NLRP1, NLRC4 and NLRP3 also intersect with cell death pathways (Bruey et al., 2007; Fernandes-Alnemri et al., 2007; Franchi et al., 2006; Fujisawa et al., 2007; Mariathasan et al., 2004; Suzuki et al., 2007; Willingham, 2007), which is reminiscent of the roles of NB-LRR proteins in causing a hypersensitive cell death response implants.

The importance of this family is further underscored by the genetic association of family members to a number of immunologic disorders. Genetic lesions in CIITA cause the immunodeficiency, Type II group A bare lymphocyte syndrome (BLS) due to a defect in the transcriptional activation of class II MHC genes (Reith and Mach, 2001; Steimle et al., 1993). Mutations in the gene encoding NLRP3 are associated with a spectrum of autoinflammatory syndromes with increasing severity: familial-cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and CINCA syndrome (Aganna et al., 2002; Dode et al., 2002; Hoffman et al., 2001)) . NOD2 is associated with Crohn's disease, Blau syndrome (Hampe et al., 2001; Hugot et al., 2001; Miceli-Richard et al., 2001; Ogura et al., 2001) asthma and psoriatric arthritis (Schreiber et al., 2005). In addition to these diseases, NLRP1 has been identified as a candidate gene for a large group of vitiligo-associated autoimmune disorders (Jin et al., 2007).

Since the discovery of this large NLR family in animals five years ago, numerous published reports support important roles in infectious diseases, autoimmune and autoinflammatory diseases. Additionally, they regulate critical cell signaling and cell death/survival pathways that act beyond the field of immunology. We anticipate the identification of both expected and unexpected functions of this family. The nomenclature described in this paper has been approved by the Human Genome Organisation (HUGO) Gene Nomenclature Committee and the Mouse Genomic Nomenclature Committee following extensive consultations with the scientific community. Concerted use of this unified nomenclature would reduce confusion and disparity, and promote the transparency of this important field. We urge all investigators to adopt the approved nomenclature in future publications and presentations.


We would like to thank all of the scientists who have taken part in the discussions leading to the approved nomenclature for this gene family. We also would like to thank the HUGO Gene Nomenclature Committee for the time they have spent discussing the issues surrounding the nomenclature of this gene family.


  • Aganna E, Martinon F, Hawkins PN, Ross JB, Swan DC, Booth DR, Lachmann HJ, Bybee A, Gaudet R, Woo P, et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 2002;46:2445–2452. [PubMed]
  • Bertin J, Nir WJ, Fischer CM, Tayber OV, Errada PR, Grant JR, Keilty JJ, Gosselin ML, Robison KE, Wong GH, et al. Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB. J Biol Chem. 1999;274:12955–12958. [PubMed]
  • Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, Kress CL, Bailly-Maitre B, Li X, Osterman A, et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell. 2007;129:45–56. [PubMed]
  • Bruey JM, Bruey-Sedano N, Newman R, Chandler S, Stehlik C, Reed JC. PAN1/NALP2/PYPAF2, an inducible inflammatory mediator that regulates NF-kappaB and caspase-1 activation in macrophages. J Biol Chem. 2004;279:51897–51907. [PubMed]
  • Dode C, Le Du N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A, et al. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet. 2002;70:1498–1506. [PubMed]
  • Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, Rosenberg S, Zhang J, Alnemri ES. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007;14:1590–1604. [PMC free article] [PubMed]
  • Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol. 2006;7:576–582. [PubMed]
  • Fritz JH, Ferrero RL, Philpott DJ, Girardin SE. Nod-like proteins in immunity, inflammation and disease. Nat Immunol. 2006;7:1250–1257. [PubMed]
  • Fujisawa A, Kambe N, Saito M, Nishikomori R, Tanizaki H, Kanazawa N, Adachi S, Heike T, Sagara J, Suda T, et al. Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells. Blood. 2007;109:2903–2911. [PubMed]
  • Grenier JM, Wang L, Manji GA, Huang WJ, Al-Garawi A, Kelly R, Carlson A, Merriam S, Lora JM, Briskin M, et al. Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1. FEBS Lett. 2002;530:73–78. [PubMed]
  • Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet. 2001;357:1925–1928. [PubMed]
  • 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;169:4088–4093. [PubMed]
  • Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29:301–305. [PMC free article] [PubMed]
  • Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411:599–603. [PubMed]
  • Inohara, Chamaillard, McDonald C, Nunez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005;74:355–383. [PubMed]
  • Inohara N, Nunez G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol. 2003;3:371–382. [PubMed]
  • Inohara N, Ogura Y, Nunez G. Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr Opin Microbiol. 2002;5:76–80. [PubMed]
  • Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007;356:1216–1225. [PubMed]
  • Jones JD, Dangl JL. The plant immune system. Nature. 2006;444:323–329. [PubMed]
  • Koonin EV, Aravind L. The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation. Trends Biochem Sci. 2000;25:223–224. [PubMed]
  • Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004;430:213–218. [PubMed]
  • Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004;117:561–574. [PubMed]
  • Martinon F, Tschopp J. NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 2005;26:447–454. [PubMed]
  • Meylan E, Tschopp J, Karin M. Intracellular pattern recognition receptors in the host response. Nature. 2006;442:39–44. [PubMed]
  • Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol. 2006;7:569–575. [PubMed]
  • Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Hafner R, Chamaillard M, Zouali H, Thomas G, Hugot JP. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29:19–20. [PubMed]
  • Molofsky AB, Byrne BG, Whitfield NN, Madigan CA, Fuse ET, Tateda K, Swanson MS. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med. 2006;203:1093–1104. [PMC free article] [PubMed]
  • Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411:603–606. [PubMed]
  • Ogura Y, Sutterwala FS, Flavell RA. The inflammasome: first line of the immune response to cell stress. Cell. 2006;126:659–662. [PubMed]
  • Pawlowski K, Pio F, Chu Z, Reed JC, Godzik A. PAAD - a new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem Sci. 2001;26:85–87. [PubMed]
  • Reith W, Mach B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol. 2001;19:331–373. [PubMed]
  • Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE. Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog. 2006;2:e18. [PubMed]
  • Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besner-Johnston A, Lefebvre C, Kang X, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell. 1995;80:167–178. [PubMed]
  • Schreiber S, Rosenstiel P, Albrecht M, Hampe J, Krawczak M. Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nat Rev Genet. 2005;6:376–388. [PubMed]
  • 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;75:135–146. [PubMed]
  • Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nunez G. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 2007;3:e111. [PubMed]
  • Ting JP, Davis BK. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol. 2005;23:387–414. [PubMed]
  • Tschopp J, Martinon F, Burns K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol. 2003;4:95–104. [PubMed]
  • Williams KL, Lich JD, Duncan JA, Reed W, Rallabhandi P, Moore C, Kurtz S, Coffield VM, Accavitti-Loper MA, Su L, et al. The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. J Biol Chem. 2005;280:39914–39924. [PMC free article] [PubMed]
  • Willingham S, Bergstralh DT, OConnor Wm., Morrison AC, Taxman DJ, Duncan JA, Barnoy S, Venkatesan MM, Flavell RA, Deshmukh M, Hoffman HM, Ting JPY. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyin and ASC. Cell Host & Microbe. 2007 [PMC free article] [PubMed]
  • Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol. 2006;7:318–325. [PubMed]