Pathway Human Homo sapiens

Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways

R-HSA-168643 in Reactome release 97: under Innate Immune System, with 60 genes placed in it by the mapping files and 2 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-168643 (mouse), R-RNO-168643 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-168643.3
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2011-06-14
Last updated: 2022-06-09
Events inside: 2, counted from the record

The innate immune system is the first line of defense against invading microorganisms, a broad specificity response characterized by the recruitment and activation of phagocytes and the release of anti-bacterial peptides. The receptors involved recognize conserved molecules present in microbes called pathogen-associated molecular patterns (PAMPs), and/or molecules that are produced as a result of tissue injury, the damage associated molecular pattern molecules (DAMPs). PAMPs are essential to the pathogen and therefore unlikely to vary. Examples are lipopolysaccharide (LPS), peptidoglycans (PGNs) and viral RNA. DAMPs include intracellular proteins, such as heat-shock proteins and extracellular matrix proteins released by tissue injury, such as hyaluronan fragments. Non-protein DAMPs include ATP, uric acid, heparin sulfate and dsDNA. The receptors for these factors are referred to collectively as pathogen- or pattern-recognition receptors (PRRs). The best studied of these are the membrane-associated Toll-like receptor family. Less well studied but more numerous are the intracellular nucleotide-binding domain, leucine rich repeat containing receptors (NLRs) also called nucleotide binding oligomerization domain (NOD)-like receptors, a family with over 20 members in humans and over 30 in mice. These recognise PAMPs/DAMPs from phagocytosed microorganisms or from intracellular infections (Kobayashi et al. 2003, Proell et al. 2008, Wilmanski et al. 2008). Some NLRs are involved in process unrelated to pathogen detection such as tissue homeostasis, apoptosis, graft-versus-host disease and early development (Kufer & Sansonetti 2011).

Structurally NLRs can be subdivided into the caspase-recruitment domain (CARD)-containing NLRCs (NODs) and the pyrin domain (PYD)-containing NLRPs (NALPs), plus outliers including ice protease (caspase-1) activating factor (IPAF) (Martinon & Tschopp, 2005). In practical terms, NLRs can be divided into the relatively well characterized NOD1/2 which signal via RIP2 primarily to NFkappaB, and the remainder, some of which participate in macromolecular structures called Inflammasomes that activate caspases. Mutations in several members of the NLR protein family have been linked to inflammatory diseases, suggesting these molecules play important roles in maintaining host-pathogen interactions and inflammatory responses.

Most NLRs have a tripartite structure consisting of a variable amino-terminal domain, a central nucleotide-binding oligomerization domain (NOD or NACHT) that is believed to mediate the formation of self oligomers, and a carboxy-terminal leucine-rich repeat (LRR) that detects PAMPs/DAMPs. In most cases the amino-terminal domain includes protein-interaction modules, such as CARD or PYD, some harbour baculovirus inhibitor repeat (BIR) or other domains. For most characterised NLRs these domains have been attributed to downstream signaling

Under resting conditions, NLRs are thought to be present in an autorepressed form, with the LRR folded back onto the NACHT domain preventing oligomerization. Accessory proteins may help maintain the inactive state. PAMP/DAMP exposure is thought to triggers conformational changes that expose the NACHT domain enabling oligomerization and recruitment of effectors, though it should be noted that due to the lack of availability of structural data, the mechanistic details of NLR activation remain largely elusive.

New terminology for NOD-like receptors was adopted by the Human Genome Organization (HUGO) in 2008 to standardize the nomenclature of NLRs. The acronym NLR, once standing for NOD-like receptor, now is an abbreviation of 'nucleotide-binding domain, leucine-rich repeat containing' protein. The term NOD-like receptor is officially outdated and replaced by NLRC where the C refers to the CARD domain. However the official gene symbols for NOD1 and NOD2 still contain NOD and this general term is still widely used.

Literature Reactome attaches

NOD-like receptors: role in innate immunity and inflammatory diseaseAnnu Rev Pathol, 2009, vol. 4, p. 365-98PubMed 18928408

Reactome's record lists 13 orthologous events, R-RNO-168643 (Rattus norvegicus), R-MMU-168643 (Mus musculus) among the species this site serves, and 11 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-28 ET · Reactome pathway browser"Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-168643 with StableID: R-HSA-168643.3 (accessed 2026-09-28 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 60 genes in this human pathway; showing 1 to 60, in pages of 100, sorted by symbol for reading. The order carries no ranking. 4 of the rows shown carry an id the identity file does not name, kept as the source wrote it.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAAMP	AuthorityHGNC:18	Mapping file id14 NCBI file	EvidenceTAS
GeneAIM2	AuthorityHGNC:357	Mapping file id9447 NCBI file	EvidenceIEA, TAS
GeneAPP	AuthorityHGNC:620	Mapping file id351 NCBI file	EvidenceTAS
GeneBCL2	AuthorityHGNC:990	Mapping file id596 NCBI file	EvidenceTAS
GeneBCL2L1	AuthorityHGNC:992	Mapping file id598 NCBI file	EvidenceTAS
GeneBIRC2	AuthorityHGNC:590	Mapping file id329 NCBI file	EvidenceTAS
GeneBIRC3	AuthorityHGNC:591	Mapping file id330 NCBI file	EvidenceTAS
GeneCARD9	AuthorityHGNC:16391	Mapping file id64170 NCBI file	EvidenceIEA
GeneCASP1	AuthorityHGNC:1499	Mapping file id834 NCBI file	EvidenceIEA, TAS
GeneCASP2	AuthorityHGNC:1503	Mapping file id835 NCBI file	EvidenceTAS
GeneCASP4	AuthorityHGNC:1505	Mapping file id837 NCBI file	EvidenceTAS
GeneCASP8	AuthorityHGNC:1509	Mapping file id841 NCBI file	EvidenceTAS
GeneCASP9	AuthorityHGNC:1511	Mapping file id842 NCBI file	EvidenceTAS
GeneCHUK	AuthorityHGNC:1974	Mapping file id1147 NCBI file	EvidenceTAS
GeneCYLD	AuthorityHGNC:2584	Mapping file id1540 NCBI file	EvidenceTAS
GeneHMOX1	AuthorityHGNC:5013	Mapping file id3162 NCBI file	EvidenceIEA
GeneHSP90AB1	AuthorityHGNC:5258	Mapping file id3326 NCBI file	EvidenceTAS
GeneIKBKB	AuthorityHGNC:5960	Mapping file id3551 NCBI file	EvidenceTAS
GeneIKBKG	AuthorityHGNC:5961	Mapping file id8517 NCBI file	EvidenceTAS
GeneIRAK1	AuthorityHGNC:6112	Mapping file id3654 NCBI file	EvidenceTAS
GeneIRAK2	AuthorityHGNC:6113	Mapping file id3656 NCBI file	EvidenceTAS
GeneITCH	AuthorityHGNC:13890	Mapping file id83737 NCBI file	EvidenceTAS
GeneMAP2K6	AuthorityHGNC:6846	Mapping file id5608 NCBI file	EvidenceTAS
GeneMAP3K7	AuthorityHGNC:6859	Mapping file id6885 NCBI file	EvidenceTAS
GeneMAPK11	AuthorityHGNC:6873	Mapping file id5600 NCBI file	EvidenceTAS
GeneMAPK12	AuthorityHGNC:6874	Mapping file id6300 NCBI file	EvidenceTAS
GeneMAPK13	AuthorityHGNC:6875	Mapping file id5603 NCBI file	EvidenceTAS
GeneMAPK14	AuthorityHGNC:6876	Mapping file id1432 NCBI file	EvidenceTAS
GeneMEFV	AuthorityHGNC:6998	Mapping file id4210 NCBI file	EvidenceTAS
GeneNFKB1	AuthorityHGNC:7794	Mapping file id4790 NCBI file	EvidenceTAS
GeneNFKB2	AuthorityHGNC:7795	Mapping file id4791 NCBI file	EvidenceTAS
GeneNLRC4	AuthorityHGNC:16412	Mapping file id58484 NCBI file	EvidenceIEA, TAS
GeneNLRP1	AuthorityHGNC:14374	Mapping file id22861 NCBI file	EvidenceTAS
GeneNLRP3	AuthorityHGNC:16400	Mapping file id114548 NCBI file	EvidenceIEA, TAS
GeneNOD1	AuthorityHGNC:16390	Mapping file id10392 NCBI file	EvidenceIEA, TAS
GeneNOD2	AuthorityHGNC:5331	Mapping file id64127 NCBI file	EvidenceIEA, TAS
GeneP2RX7	AuthorityHGNC:8537	Mapping file id5027 NCBI file	EvidenceIEA, TAS
GenePANX1	AuthorityHGNC:8599	Mapping file id24145 NCBI file	EvidenceTAS
GenePSTPIP1	AuthorityHGNC:9580	Mapping file id9051 NCBI file	EvidenceTAS
GenePYCARD	AuthorityHGNC:16608	Mapping file id29108 NCBI file	EvidenceIEA, TAS
GeneRELA	AuthorityHGNC:9955	Mapping file id5970 NCBI file	EvidenceTAS
GeneRIPK2	AuthorityHGNC:10020	Mapping file id8767 NCBI file	EvidenceIEA, TAS
GeneRPS27A	AuthorityHGNC:10417	Mapping file id6233 NCBI file	EvidenceTAS
GeneSUGT1	AuthorityHGNC:16987	Mapping file id10910 NCBI file	EvidenceTAS
GeneTAB1	AuthorityHGNC:18157	Mapping file id10454 NCBI file	EvidenceTAS
GeneTAB2	AuthorityHGNC:17075	Mapping file id23118 NCBI file	EvidenceTAS
GeneTAB3	AuthorityHGNC:30681	Mapping file id257397 NCBI file	EvidenceTAS
GeneTNFAIP3	AuthorityHGNC:11896	Mapping file id7128 NCBI file	EvidenceTAS
GeneTRAF6	AuthorityHGNC:12036	Mapping file id7189 NCBI file	EvidenceTAS
GeneTXN	AuthorityHGNC:12435	Mapping file id7295 NCBI file	EvidenceIEA, TAS
GeneTXNIP	AuthorityHGNC:16952	Mapping file id10628 NCBI file	EvidenceIEA, TAS
GeneUBA52	AuthorityHGNC:12458	Mapping file id7311 NCBI file	EvidenceTAS
GeneUBB	AuthorityHGNC:12463	Mapping file id7314 NCBI file	EvidenceTAS
GeneUBC	AuthorityHGNC:12468	Mapping file id7316 NCBI file	EvidenceTAS
GeneUBE2N	AuthorityHGNC:12492	Mapping file id7334 NCBI file	EvidenceTAS
GeneUBE2V1	AuthorityHGNC:12494	Mapping file id7335 NCBI file	EvidenceTAS
Geneno symbol in the identity file	Authoritynone	Mapping file id1253480 NCBI file	EvidenceIEA, TAS
Geneno symbol in the identity file	Authoritynone	Mapping file id1254294 NCBI file	EvidenceIEA, TAS
Geneno symbol in the identity file	Authoritynone	Mapping file id1254395 NCBI file	EvidenceIEA, TAS
Geneno symbol in the identity file	Authoritynone	Mapping file id43740575 NCBI file	EvidenceTAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Innate Immune SystemR-HSA-1682491,207 genes

Children

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.