The NLR Gene Family: A Standard Nomenclature

Abstract

Immune regulatory proteins such as CIITA, NAIP, IPAF, NOD1, NOD2, NALP1, and cryopyrin (also known as NALP3) are members of a family characterized by the presence of a NACHT nucleotide-binding domain (NBD) and leucine-rich repeats (LRRs). 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 death. Currently, a variety of different names are used to describe the products encoded by the NBD and LRR containing gene family, its subfamilies, and individual genes, including CATERPILLER (CLR), NOD-LRR, NACHT-LRR, NOD-like receptor, CARD, NALP, NOD, PAN, and PYPAF. This lack of consistency has led to a pressing need to unify the nomenclature for this gene family. Consequently, we propose a standardized nomenclature, NLR, which stands for the nucleotide-binding domain and leucine-rich repeat containing gene family. The NLR family includes several subfamilies distinguishable by their N-terminal effector domains. There are four recognizable NLR N-terminal domains: acidic transactivation domain, pyrin domain, caspase recruitment domain (CARD), and baculoviral inhibitory repeat (BIR)-like domains (see Table 1 for the human NLR genes). 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 largest pyrin-containing subfamily has been named PAN, NALP, and PYPAF; members of the CARD-containing subfamily have been named CARDs or NODs; the BIR-containing subfamily has been named NAIP or BIRC.Table 1New Approved Designations for the Human NLR Family MembersNLR FamilyHGNC-Approved SymbolApproved NameOther Names and AliasesDomain OrganizationProtein SequenceNLRACIITAclass II, major histocompatibility complex, transactivatorNLRA; MHC2TA; C2TA(CARD)-AD-NACHT-NAD-LRRNP_000237NLRBNAIPNLR family, apoptosis inhibitory proteinNLRB1; BIRC1; CLR5.1BIR3x-NACHT-LRRNP_004527NLRCNOD1nucleotide-binding oligomerization domain containing 1NLRC1; CARD4; CLR7.1CARD-NACHT-NAD-LRRNP_006083NLRCNOD2nucleotide-binding oligomerization domain containing 2NLRC2; CARD15; CD; BLAU; IBD1; PSORAS1; CLR16.3CARD2x-NACHT-NAD-LRRNP_071445NLRCNLRC3NLR family, CARD domain containing 3NOD3; CLR16.2CARD-NACHT-NAD-LRRNP_849172NLRCNLRC4NLR family, CARD domain containing 4CARD12; CLAN; CLR2.1; IPAFCARD-NACHT-NAD-LRRNP_067032NLRCNLRC5NLR family, CARD domain containing 5NOD27; CLR16.1CARD-NACHT-NAD-LRRNP_115582NLRPNLRP1NLR family, pyrin domain containing 1NALP1; DEFCAP; NAC; CARD7; CLR17.1PYD-NACHT-NAD-LRR-FIIND-CARDNP_127497NLRPNLRP2NLR family, pyrin domain containing 2NALP2; PYPAF2; NBS1; PAN1; CLR19.9PYD-NACHT-NAD-LRRNP_060322NLRPNLRP3NLR family, pyrin domain containing 3CIAS1; PYPAF1; Cryopyrin; CLR1.1; NALP3PYD-NACHT-NAD-LRRNP_004886NLRPNLRP4NLR family, pyrin domain containing 4NALP4; PYPAF4; PAN2; RNH2; CLR19.5PYD-NACHT-NAD-LRRNP_604393NLRPNLRP5NLR family, pyrin domain containing 5NALP5; PYPAF8; MATER; PAN11; CLR19.8PYD-NACHT-NAD-LRRNP_703148NLRPNLRP6NLR family, pyrin domain containing 6NALP6; PYPAF5; PAN3; CLR11.4PYD-NACHT-NAD-LRRNP_612202NLRPNLRP7NLR family, pyrin domain containing 7NALP7; PYPAF3; NOD12; PAN7; CLR19.4PYD-NACHT-NAD-LRRNP_996611NLRPNLRP8NLR family, pyrin domain containing 8NALP8; PAN4; NOD16; CLR19.2PYD-NACHT-NAD-LRRNP_789781NLRPNLRP9NLR family, pyrin domain containing 9NALP9; NOD6; PAN12; CLR19.1PYD-NACHT-NAD-LRRNP_789790NLRPNLRP10NLR family, pyrin domain containing 10NALP10; PAN5; NOD8; PYNOD; CLR11.1PYD-NACHT-NADNP_789791NLRPNLRP11NLR family, pyrin domain containing 11NALP11; PYPAF6; NOD17; PAN10; CLR19.6PYD-NACHT-NAD-LRRNP_659444NLRPNLRP12NLR family, pyrin domain containing 12NALP12; PYPAF7; Monarch1; RNO2; PAN6; CLR19.3PYD-NACHT-NAD-LRRNP_653288NLRPNLRP13NLR family, pyrin domain containing 13NALP13; NOD14; PAN13; CLR19.7PYD-NACHT-NAD-LRRNP_789780NLRPNLRP14NLR family, pyrin domain containing 14NALP14; NOD5; PAN8; CLR11.2PYD-NACHT-NAD-LRRNP_789792NLRXNLRX1NLR family member X1NOD9; CLR11.3X-NACHT-NAD-LRRNP_078894The following abbreviations are used: AD, acidic activation domain CARD, caspase activating and recruitment domain; LRR, leucine-rich repeat; NACHT, domain present in NAIP, CIITA, HET-E, and TP-1; BIR, baculovirus inhibitor of apoptosis repeat; PYD, pyrin domain; and NAD, NACHT-associated domain. Open table in a new tab The following abbreviations are used: AD, acidic activation domain CARD, caspase activating and recruitment domain; LRR, leucine-rich repeat; NACHT, domain present in NAIP, CIITA, HET-E, and TP-1; BIR, baculovirus inhibitor of apoptosis repeat; PYD, pyrin domain; and NAD, NACHT-associated domain. In consultation with over 100 scientists, through a stepwise voting process organized by the Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC) and conducted via email and updated web pages, a new nomenclature system for human and mouse NLR genes has been agreed upon (see Table S1 available online for human and mouse NLR genes). It was agreed that the family name “nucleotide-binding domain and leucine-rich repeat containing” should be used to highlight these two evolutionarily conserved domains and to reflect the similarity of the NLR family to the plant NB-LRR proteins. Furthermore, the consensus of opinion was that a subfamily-derived nomenclature system based on the N-terminal effector domains should be implemented. Consequently, four subfamily designations have been approved: NLRA, NLR family, acidic domain containing; NLRB, NLR family, BIR domain containing; NLRC, NLR family, CARD domain containing; NLRP, NLR family, pyrin domain containing; NLRX, NLR family with no strong homology to the N-terminal domain of any other NLR subfamily member (Table 1). Each member within a subfamily is given a number, e.g., NLRP1. Four members of the NLR family, CIITA, NAIP, NOD1, and NOD2, have not been renamed. These four genes are associated with a large volume of literature, and it was agreed that renaming these would cause confusion in the literature. However, each of these genes has been given a subfamily alias to enable electronic data-retrieval systems to link these four genes to the NLR gene family. Clearly related genes, such as NLRP10 and Naip3-6, that do not encode NBD and/or LRR are included for completeness and historic reasons. To distinguish between human and mouse NLR genes, the human genes are written in upper case, whereas murine orthologs are distinguished from the human genes by the use of uppercase for the first letter only, followed by lowercase (Table S1). 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. The nomenclature described in this paper has been approved by the HGNC and the Mouse Genomic Nomenclature Committee. Concerted use of this unified nomenclature will 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 HGNC (http://www.genenames.org) for the time they have spent discussing the issues surrounding the nomenclature of this gene family. Download .pdf (.02 MB) Help with pdf files Document S1. New Approved Designations for Human and Mouse NLR Family Members