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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)

Identity

Other namesIpaf
CARD12
CLAN
CLR2.1
HGNC (Hugo) NLRC4
LocusID (NCBI) 58484
Atlas_Id 43189
Location 2p22.3  [Link to chromosome band 2p22]
Location_base_pair Starts at 32449518 and ends at 32489949 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 2016)
MSN (Xq12) / NLRC4 (2p22.3)

DNA/RNA

 
  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.

Protein

 
  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.

Mutations

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

Bibliography

CLAN, a novel human CED-4-like gene.
Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC
Genomics. 2001 ; 75 (1-3) : 77-83.
PMID 11472070
 
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
 
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
 
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
 
Multiple roles of CLAN (caspase-associated recruitment domain, leucine-rich repeat, and NAIP CIIA HET-E, and TP1-containing protein) in the mammalian innate immune response.
Damiano JS, Newman RM, Reed JC
Journal of immunology (Baltimore, Md. : 1950). 2004 ; 173 (10) : 6338-6345.
PMID 15528373
 
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
 
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
 
Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM
Nature. 2004 ; 430 (6996) : 213-218.
PMID 15190255
 
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
 
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
 
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
 
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
 
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
 
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
 
Cytosolic detection of flagellin: a deadly twist.
Roy CR, Zamboni DS
Nature immunology. 2006 ; 7 (6) : 549-551.
PMID 16715062
 
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
 
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
 
Innate recognition of intracellular bacteria.
Delbridge LM, O'Riordan MX
Current opinion in immunology. 2007 ; 19 (1) : 10-16.
PMID 17126540
 
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
 
The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation.
Lamkanfi M, Amer A, Kanneganti TD, Muñoz-Planillo R, Chen G, Vandenabeele P, Fortier A, Gros P, Nez G
Journal of immunology (Baltimore, Md. : 1950). 2007 ; 178 (12) : 8022-8027.
PMID 17548639
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 

Citation

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 : http://AtlasGeneticsOncology.org/Genes/NLRC4ID43189ch2p22.html


External links

Nomenclature
HGNC (Hugo)NLRC4   16412
Cards
AtlasNLRC4ID43189ch2p22
Entrez_Gene (NCBI)NLRC4  58484  NLR family, CARD domain containing 4
AliasesAIFEC; CARD12; CLAN; CLAN1; 
CLANA; CLANB; CLANC; CLAND; CLR2.1; FCAS4; IPAF
GeneCards (Weizmann)NLRC4
Ensembl hg19 (Hinxton)ENSG00000091106 [Gene_View]  chr2:32449518-32489949 [Contig_View]  NLRC4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000091106 [Gene_View]  chr2:32449518-32489949 [Contig_View]  NLRC4 [Vega]
ICGC DataPortalENSG00000091106
TCGA cBioPortalNLRC4
AceView (NCBI)NLRC4
Genatlas (Paris)NLRC4
WikiGenes58484
SOURCE (Princeton)NLRC4
Genomic and cartography
GoldenPath hg19 (UCSC)NLRC4  -     chr2:32449518-32489949 -  2p22.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)NLRC4  -     2p22.3   [Description]    (hg38-Dec_2013)
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)NC_000002 NC_018913 NG_041780 NT_022184 NW_004929300
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]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)58484
GTEX Portal (Tissue expression)NLRC4
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NPP4 (Uniprot)
NextProtQ9NPP4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9NPP4
Splice isoforms : SwissVarQ9NPP4 (Swissvar)
PhosPhoSitePlusQ9NPP4
Domaine pattern : Prosite (Expaxy)CARD (PS50209)    NACHT (PS50837)   
Domains : Interpro (EBI)CARD    DEATH-like_dom    L_dom-like    NACHT_NTPase    P-loop_NTPase   
Domain families : Pfam (Sanger)CARD (PF00619)   
Domain families : Pfam (NCBI)pfam00619   
DMDM Disease mutations58484
Blocks (Seattle)NLRC4
SuperfamilyQ9NPP4
Human Protein AtlasENSG00000091106
Peptide AtlasQ9NPP4
HPRD06014
IPIIPI00293227   IPI00217430   IPI00217431   IPI00217432   
Protein Interaction databases
DIP (DOE-UCLA)Q9NPP4
IntAct (EBI)Q9NPP4
FunCoupENSG00000091106
BioGRIDNLRC4
STRING (EMBL)NLRC4
ZODIACNLRC4
Ontologies - Pathways
QuickGOQ9NPP4
Ontology : AmiGOmagnesium ion binding  activation of innate immune response  ubiquitin-protein transferase activity  cysteine-type endopeptidase inhibitor activity  protein binding  ATP binding  intracellular  nucleus  cytosol  cytosol  spindle microtubule  activation of cysteine-type endopeptidase activity involved in apoptotic process  inflammatory response  regulation of signal transduction  detection of bacterium  protein ubiquitination  defense response to bacterium  identical protein binding  protein homodimerization activity  regulation of apoptotic process  positive regulation of apoptotic process  innate immune response  interleukin-1 beta secretion  positive regulation of NF-kappaB transcription factor activity  protein homooligomerization  pyroptosis  IPAF inflammasome complex  IPAF inflammasome complex  mitotic spindle assembly  inhibition of cysteine-type endopeptidase activity involved in apoptotic process  
Ontology : EGO-EBImagnesium ion binding  activation of innate immune response  ubiquitin-protein transferase activity  cysteine-type endopeptidase inhibitor activity  protein binding  ATP binding  intracellular  nucleus  cytosol  cytosol  spindle microtubule  activation of cysteine-type endopeptidase activity involved in apoptotic process  inflammatory response  regulation of signal transduction  detection of bacterium  protein ubiquitination  defense response to bacterium  identical protein binding  protein homodimerization activity  regulation of apoptotic process  positive regulation of apoptotic process  innate immune response  interleukin-1 beta secretion  positive regulation of NF-kappaB transcription factor activity  protein homooligomerization  pyroptosis  IPAF inflammasome complex  IPAF inflammasome complex  mitotic spindle assembly  inhibition of cysteine-type endopeptidase activity involved in apoptotic process  
Pathways : KEGGNOD-like receptor signaling pathway    Salmonella infection    Legionellosis   
NDEx Network
Atlas of Cancer Signalling NetworkNLRC4
Wikipedia pathwaysNLRC4
Orthology - Evolution
OrthoDB58484
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: TCGAMSN Xq12 NLRC4 2p22.3 BRCA
Polymorphisms : SNP, variants
NCBI Variation ViewerNLRC4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NLRC4
dbVarNLRC4
ClinVarNLRC4
1000_GenomesNLRC4 
Exome Variant ServerNLRC4
ExAC (Exome Aggregation Consortium)NLRC4 (select the gene name)
Genetic variants : HAPMAP58484
Genomic Variants (DGV)NLRC4 [DGVbeta]
Mutations
ICGC Data PortalNLRC4 
TCGA Data PortalNLRC4 
Broad Tumor PortalNLRC4
OASIS PortalNLRC4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNLRC4 
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)
intoGenNLRC4
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)2:32449518-32489949  ENSG00000091106
CONAN: Copy Number AnalysisNLRC4 
Mutations and Diseases : HGMDNLRC4
OMIM606831    616050    616115   
MedgenNLRC4
Genetic Testing Registry NLRC4
NextProtQ9NPP4 [Medical]
TSGene58484
GENETestsNLRC4
Huge Navigator NLRC4 [HugePedia]
snp3D : Map Gene to Disease58484
BioCentury BCIQNLRC4
ClinGenNLRC4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD58484
Chemical/Pharm GKB GenePA162397671
Clinical trialNLRC4
Miscellaneous
canSAR (ICR)NLRC4 (select the gene name)
Probes
Litterature
PubMed33 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNLRC4
EVEXNLRC4
GoPubMedNLRC4
iHOPNLRC4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue May 31 15:46:27 CEST 2016

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