Atlas of Genetics and Cytogenetics in Oncology and Haematology

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NLRC4 (NLR Family, CARD domain containing 4)

Written2007-07Yatender Kumar, Vegesna Radha, Ghanshyam Swarup
Center for cellular, molecular biology, uppal road, Hyderabad- 500 007, India

(Note : for Links provided by Atlas : click)


caspase recruitment domain family
Alias_symbol (synonym)CLAN1
Other aliasIpaf
LocusID (NCBI) 58484
Atlas_Id 43189
Location 2p22.3  [Link to chromosome band 2p22]
Location_base_pair Starts at 32224449 and ends at 32265743 bp from pter ( according to hg19-Feb_2009)  [Mapping NLRC4.png]
Local_order Galactose enzyme activator 2p22-p11
Solute carrier family 30(Zinc transporter), member 2p22.3
RH-II GuB pseudogene 2p22-p21
NLRC4 2p22-p21
Yip domain family, member 4 2p22.3
  Human Chromosome 2 map depicting the position of NLRC4.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
MSN (Xq12) / NLRC4 (2p22.3)


  Schematic showing genome organization of NLRC4 gene.
Description The NLRC4 gene is comprised of 9 exons, spanning 41.3kb on chromosome 2p21-p22.
Transcription 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.
Pseudogene Not Known.


  Schematic showing domain organization of NLRC4 protein.
Description 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.
Expression 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.
Localisation Cytosolic.
Function 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.
Homology 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.


Germinal Not known in H.sapiens.
Somatic Not known in H.sapiens.


Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf.
Amer A, Franchi L, Kanneganti TD, Body-Malapel M, Ozören N, Brady G, Meshinchi S, Jagirdar R, Gewirtz A, Akira S, Nez G
The Journal of biological chemistry. 2006 ; 281 (46) : 35217-35223.
PMID 16984919
Restriction of Legionella pneumophila growth in macrophages requires the concerted action of cytokine and Naip5/Ipaf signalling pathways.
Coers J, Vance RE, Fontana MF, Dietrich WF
Cellular microbiology. 2007 ; 9 (10) : 2344-2357.
PMID 17506816
Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses.
Damiano JS, Oliveira V, Welsh K, Reed JC
The Biochemical journal. 2004 ; 381 (Pt 1) : 213-219.
PMID 15107016
Innate recognition of intracellular bacteria.
Delbridge LM, O'Riordan MX
Current opinion in immunology. 2007 ; 19 (1) : 10-16.
PMID 17126540
Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages.
Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozören N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Nez G
Nature immunology. 2006 ; 7 (6) : 576-582.
PMID 16648852
Nod-like proteins in immunity, inflammation and disease.
Fritz JH, Ferrero RL, Philpott DJ, Girardin SE
Nature immunology. 2006 ; 7 (12) : 1250-1257.
PMID 17110941
Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis.
Geddes BJ, Wang L, Huang WJ, Lavellee M, Manji GA, Brown M, Jurman M, Cao J, Morgenstern J, Merriam S, Glucksmann MA, DiStefano PS, Bertin J
Biochemical and biophysical research communications. 2001 ; 284 (1) : 77-82.
PMID 11374873
Ipaf is upregulated by tumor necrosis factor-alpha in human leukemia cells.
Gutierrez O, Pipaon C, Fernandez-Luna JL
FEBS letters. 2004 ; 568 (1-3) : 79-82.
PMID 15196924
NOD-LRR proteins: role in host-microbial interactions and inflammatory disease.
Inohara, Chamaillard, McDonald C, Nuñez G
Annual review of biochemistry. 2005 ; 74 : 355-383.
PMID 15952891
Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling.
Kanneganti TD, Lamkanfi M, Kim YG, Chen G, Park JH, Franchi L, Vandenabeele P, Nez G
Immunity. 2007 ; 26 (4) : 433-443.
PMID 17433728
Caspase-1 inflammasomes in infection and inflammation.
Lamkanfi M, Kanneganti TD, Franchi L, Nez G
Journal of leukocyte biology. 2007 ; 82 (2) : 220-225.
PMID 17442855
Nucleotide binding to CARD12 and its role in CARD12-mediated caspase-1 activation.
Lu C, Wang A, Wang L, Dorsch M, Ocain TD, Xu Y
Biochemical and biophysical research communications. 2005 ; 331 (4) : 1114-1119.
PMID 15882992
ASC, Ipaf and Cryopyrin/Nalp3: bona fide intracellular adapters of the caspase-1 inflammasome.
Mariathasan S
Microbes and infection / Institut Pasteur. 2007 ; 9 (5) : 664-671.
PMID 17382568
Inflammatory caspases and inflammasomes: master switches of inflammation.
Martinon F, Tschopp J
Cell death and differentiation. 2007 ; 14 (1) : 10-22.
PMID 16977329
ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis.
Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M, Zhu L, Katsuyama T, Sagara J, Taniguchi S, Gumucio DL, Nez G, Inohara N
Biochemical and biophysical research communications. 2003 ; 303 (1) : 69-73.
PMID 12646168
A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses.
Mayor A, Martinon F, De Smedt T, Pétrilli V, Tschopp J
Nature immunology. 2007 ; 8 (5) : 497-503.
PMID 17435760
Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf.
Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A
Nature immunology. 2006 ; 7 (6) : 569-575.
PMID 16648853
TLRS in the gut. II. Flagellin-induced inflammation and antiapoptosis.
Neish AS
American journal of physiology. Gastrointestinal and liver physiology. 2007 ; 292 (2) : G462-G466.
PMID 17082224
The inflammasome: first line of the immune response to cell stress.
Ogura Y, Sutterwala FS, Flavell RA
Cell. 2006 ; 126 (4) : 659-662.
PMID 16923387
Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.
Pétrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J
Cell death and differentiation. 2007 ; 14 (9) : 1583-1589.
PMID 17599094
Regulation of p73 by Hck through kinase-dependent and independent mechanisms.
Paliwal P, Radha V, Swarup G
BMC molecular biology. 2007 ; 8 : page 45.
PMID 17535448
Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1.
Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES
The Journal of biological chemistry. 2001 ; 276 (30) : 28309-28313.
PMID 11390368
The role of altered microbial signaling via mutant NODs in intestinal inflammation.
Rescigno M, Nieuwenhuis EE
Current opinion in gastroenterology. 2007 ; 23 (1) : 21-26.
PMID 17133080
Cytosolic detection of flagellin: a deadly twist.
Roy CR, Zamboni DS
Nature immunology. 2006 ; 7 (6) : 549-551.
PMID 16715062
Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis.
Sadasivam S, Gupta S, Radha V, Batta K, Kundu TK, Swarup G
Oncogene. 2005 ; 24 (4) : 627-636.
PMID 15580302
Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis.
Thalappilly S, Sadasivam S, Radha V, Swarup G
The FEBS journal. 2006 ; 273 (12) : 2766-2778.
PMID 16817903
TIR, CARD and PYRIN: three domains for an antimicrobial triad.
Werts C, Girardin SE, Philpott DJ
Cell death and differentiation. 2006 ; 13 (5) : 798-815.
PMID 16528382


This paper should be referenced as such :
Kumar, Y ; Radha, V ; Swarup, G
NLRC4 (NLR Family, CARD domain containing 4)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(1):56-58.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(X;2)(q11;p22) MSN/NLRC4

External links

HGNC (Hugo)NLRC4   16412
Entrez_Gene (NCBI)NLRC4  58484  NLR family CARD domain containing 4
GeneCards (Weizmann)NLRC4
Ensembl hg19 (Hinxton)ENSG00000091106 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000091106 [Gene_View]  ENSG00000091106 [Sequence]  chr2:32224449-32265743 [Contig_View]  NLRC4 [Vega]
ICGC DataPortalENSG00000091106
TCGA cBioPortalNLRC4
Genatlas (Paris)NLRC4
SOURCE (Princeton)NLRC4
Genetics Home Reference (NIH)NLRC4
Genomic and cartography
GoldenPath hg38 (UCSC)NLRC4  -     chr2:32224449-32265743 -  2p22.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NLRC4  -     2p22.3   [Description]    (hg19-Feb_2009)
EnsemblNLRC4 - 2p22.3 [CytoView hg19]  NLRC4 - 2p22.3 [CytoView hg38]
Mapping of homologs : NCBINLRC4 [Mapview hg19]  NLRC4 [Mapview hg38]
OMIM606831   616050   616115   
Gene and transcription
Genbank (Entrez)AF376061 AK095467 AK292673 AK314762 AL389934
RefSeq transcript (Entrez)NM_001199138 NM_001199139 NM_001302504 NM_021209
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)NLRC4
Cluster EST : UnigeneHs.574741 [ NCBI ]
CGAP (NCI)Hs.574741
Alternative Splicing GalleryENSG00000091106
Gene ExpressionNLRC4 [ NCBI-GEO ]   NLRC4 [ EBI - ARRAY_EXPRESS ]   NLRC4 [ SEEK ]   NLRC4 [ MEM ]
Gene Expression Viewer (FireBrowse)NLRC4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)58484
GTEX Portal (Tissue expression)NLRC4
Human Protein AtlasENSG00000091106-NLRC4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NPP4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9NPP4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9NPP4
Splice isoforms : SwissVarQ9NPP4
Domaine pattern : Prosite (Expaxy)CARD (PS50209)    NACHT (PS50837)   
Domains : Interpro (EBI)CARD    DEATH-like_dom_sf    LRR_dom_sf    NACHT_NTPase    P-loop_NTPase   
Domain families : Pfam (Sanger)CARD (PF00619)   
Domain families : Pfam (NCBI)pfam00619   
Conserved Domain (NCBI)NLRC4
DMDM Disease mutations58484
Blocks (Seattle)NLRC4
Human Protein Atlas [tissue]ENSG00000091106-NLRC4 [tissue]
Peptide AtlasQ9NPP4
IPIIPI00293227   IPI00217430   IPI00217431   IPI00217432   
Protein Interaction databases
IntAct (EBI)Q9NPP4
Ontologies - Pathways
Ontology : AmiGOmagnesium ion binding  activation of innate immune response  protein binding  ATP binding  intracellular  cytosol  cytosol  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  inflammatory response  detection of bacterium  protein ubiquitination  defense response to bacterium  identical protein binding  protein homodimerization activity  regulation of apoptotic process  positive regulation of apoptotic process  interleukin-1 beta secretion  positive regulation of NF-kappaB transcription factor activity  protein homooligomerization  pyroptosis  IPAF inflammasome complex  IPAF inflammasome complex  
Ontology : EGO-EBImagnesium ion binding  activation of innate immune response  protein binding  ATP binding  intracellular  cytosol  cytosol  apoptotic process  activation of cysteine-type endopeptidase activity involved in apoptotic process  inflammatory response  detection of bacterium  protein ubiquitination  defense response to bacterium  identical protein binding  protein homodimerization activity  regulation of apoptotic process  positive regulation of apoptotic process  interleukin-1 beta secretion  positive regulation of NF-kappaB transcription factor activity  protein homooligomerization  pyroptosis  IPAF inflammasome complex  IPAF inflammasome complex  
Pathways : KEGGNOD-like receptor signaling pathway    Salmonella infection    Legionellosis   
NDEx NetworkNLRC4
Atlas of Cancer Signalling NetworkNLRC4
Wikipedia pathwaysNLRC4
Orthology - Evolution
GeneTree (enSembl)ENSG00000091106
Phylogenetic Trees/Animal Genes : TreeFamNLRC4
Homologs : HomoloGeneNLRC4
Homology/Alignments : Family Browser (UCSC)NLRC4
Gene fusions - Rearrangements
Fusion : MitelmanMSN/NLRC4 [Xq12/2p22.3]  [t(X;2)(q11;p22)]  
Fusion PortalMSN Xq12 NLRC4 2p22.3 BRCA
Fusion : QuiverNLRC4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNLRC4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NLRC4
Exome Variant ServerNLRC4
ExAC (Exome Aggregation Consortium)ENSG00000091106
GNOMAD BrowserENSG00000091106
Varsome BrowserNLRC4
Genetic variants : HAPMAP58484
Genomic Variants (DGV)NLRC4 [DGVbeta]
DECIPHERNLRC4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNLRC4 
ICGC Data PortalNLRC4 
TCGA Data PortalNLRC4 
Broad Tumor PortalNLRC4
OASIS PortalNLRC4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNLRC4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNLRC4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NLRC4
DgiDB (Drug Gene Interaction Database)NLRC4
DoCM (Curated mutations)NLRC4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NLRC4 (select a term)
NCG5 (London)NLRC4
Cancer3DNLRC4(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM606831    616050    616115   
Orphanet23330    10608   
Genetic Testing Registry NLRC4
NextProtQ9NPP4 [Medical]
Target ValidationNLRC4
Huge Navigator NLRC4 [HugePedia]
snp3D : Map Gene to Disease58484
BioCentury BCIQNLRC4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD58484
Chemical/Pharm GKB GenePA162397671
Clinical trialNLRC4
canSAR (ICR)NLRC4 (select the gene name)
PubMed45 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 12 18:07:25 CEST 2018

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