NLRC4 (NLR Family, CARD domain containing 4)

2007-07-01   Yatender Kumar , Vegesna Radha , Ghanshyam Swarup 

Center for cellular, molecular biology, uppal road, Hyderabad- 500 007, India


Atlas Image
Human Chromosome 2 map depicting the position of NLRC4.


Atlas Image
Schematic showing genome organization of NLRC4 gene.


The NLRC4 gene is comprised of 9 exons, spanning 41.3kb on chromosome 2p21-p22.


Four isoforms arising due to alternate splicing of NLRC4/CLAN cDNA have been identified in Homo sapiens. The longest transcript termed CLAN-A is 3.370kb with an ORF encoding 1024 amino acids. CLAN-B, C and D have exon 4 spliced selectively to other exons forming shorter transcripts. Tumor suppressor p53 activates transcription of full length NLRC4 mRNA by binding to a site in the minimal promoter.


Not Known.


Atlas Image
Schematic showing domain organization of NLRC4 protein.


NLRC4 encodes a protein of 1024 residues with a predicted molecular mass of 112kDa. NLRC4 contains an N-terminal CARD (caspase activation and recruitment domain), a central NBD (nucleotide binding domain) and an LRR (leucine rich repeat) domain containing 13 leucine rich repeats at its carboxy terminus. The NBD is essential for activation of caspase-1. The CARD of NLRC4 is involved in interaction with itself and other CARD containing proteins and LRR domain is believed to be a regulatory domain.


NLRC4 is highly expressed in the bone marrow and lung and to a lesser extent in lymph nodes, placenta, and spleen. TNF-a, Doxorubicin, UV radiation and p53 or p73 over expression induce mRNA of NLRC4 in many cell lines. NLRC4 is also induced by over expression of the tyrosine phosphatase, TC-45, which activates p53. P53 response elements have been identified upstream of the transcription start site of the NLRC4 gene.




NLRC4 associates with caspase-1 and several other CARD containing proteins, including ASC. The LRR domain may exert an auto inhibitory function on NLRC4 as truncation of this domain makes the protein constitutively active.
NLRC4 is involved in the regulation of caspase-1, which is activated within the "inflammasome", a complex comprising several adaptors and permitting pro-IL-1beta processing and secretion of mature IL-1beta.
It is required for the activation of caspase-1 and IL-1beta secretion in response to bacterial flagellin.
It is involved in restriction of Legionella replication through the regulation of phagosome maturation. NLRC4 knock out mice are resistant to Salmonella typhimurium induced endotoxic shock.
NLRC4 is one of the mediators of the p53-induced apoptosis.
It is also known to have caspase-1 independent functions.


The CARD of NLRC4 bears significant homology to the CARDs of Caspase-1, cIAP-1 and cIAP-2, and ICEBERG. The NBD domain of NLRC4 shows high similarity to the NBD domains of NAIP, NOD1 and NOD2.



Not known in H.sapiens.


Not known in H.sapiens.

Implicated in


Pubmed IDLast YearTitleAuthors
169849192006Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf.Amer A et al
175068162007Restriction of Legionella pneumophila growth in macrophages requires the concerted action of cytokine and Naip5/Ipaf signalling pathways.Coers J et al
151070162004Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses.Damiano JS et al
171265402007Innate recognition of intracellular bacteria.Delbridge LM et al
166488522006Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages.Franchi L et al
171109412006Nod-like proteins in immunity, inflammation and disease.Fritz JH et al
113748732001Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis.Geddes BJ et al
151969242004Ipaf is upregulated by tumor necrosis factor-alpha in human leukemia cells.Gutierrez O et al
159528912005NOD-LRR proteins: role in host-microbial interactions and inflammatory disease.Inohara et al
174337282007Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling.Kanneganti TD et al
174428552007Caspase-1 inflammasomes in infection and inflammation.Lamkanfi M et al
158829922005Nucleotide binding to CARD12 and its role in CARD12-mediated caspase-1 activation.Lu C et al
173825682007ASC, Ipaf and Cryopyrin/Nalp3: bona fide intracellular adapters of the caspase-1 inflammasome.Mariathasan S et al
169773292007Inflammatory caspases and inflammasomes: master switches of inflammation.Martinon F et al
126461682003ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis.Masumoto J et al
174357602007A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses.Mayor A et al
166488532006Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf.Miao EA et al
170822242007TLRS in the gut. II. Flagellin-induced inflammation and antiapoptosis.Neish AS et al
169233872006The inflammasome: first line of the immune response to cell stress.Ogura Y et al
175990942007Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.Pétrilli V et al
175354482007Regulation of p73 by Hck through kinase-dependent and independent mechanisms.Paliwal P et al
113903682001Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1.Poyet JL et al
171330802007The role of altered microbial signaling via mutant NODs in intestinal inflammation.Rescigno M et al
167150622006Cytosolic detection of flagellin: a deadly twist.Roy CR et al
155803022005Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis.Sadasivam S et al
168179032006Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis.Thalappilly S et al
165283822006TIR, CARD and PYRIN: three domains for an antimicrobial triad.Werts C et al

Other Information

Locus ID:

NCBI: 58484
MIM: 606831
HGNC: 16412
Ensembl: ENSG00000091106


dbSNP: 58484
ClinVar: 58484
TCGA: ENSG00000091106


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Salmonella infectionKEGGko05132
Salmonella infectionKEGGhsa05132
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
The IPAF inflammasomeREACTOMER-HSA-844623
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
TP53 Regulates Transcription of Cell Death GenesREACTOMER-HSA-5633008
TP53 Regulates Transcription of Caspase Activators and CaspasesREACTOMER-HSA-6803207

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
219185122011The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus.402
232156452013Recognition of bacteria by inflammasomes.126
252179602014Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.102
230123632012Formation and structure of a NAIP5-NLRC4 inflammasome induced by direct interactions with conserved N- and C-terminal regions of flagellin.62
253857542014An inherited mutation in NLRC4 causes autoinflammation in human and mice.61
269728472016IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis.59
225477062012NLRC4 inflammasome-mediated production of IL-1β modulates mucosal immunity in the lung against gram-negative bacterial infection.54
184536012008NAIP and Ipaf control Legionella pneumophila replication in human cells.48
277082832016Obesity-associated NLRC4 inflammasome activation drives breast cancer progression.41
203491222010Innate immune detection of bacterial virulence factors via the NLRC4 inflammasome.36


Yatender Kumar ; Vegesna Radha ; Ghanshyam Swarup

NLRC4 (NLR Family, CARD domain containing 4)

Atlas Genet Cytogenet Oncol Haematol. 2007-07-01

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