NLRC4

NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.^[5][6]

NLRC4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4KXF
Identifiers
Aliases	NLRC4, CARD12, CLAN, CLAN1, CLANA, CLANB, CLANC, CLAND, CLR2.1, IPAF, AIFEC, FCAS4, NLR family, CARD domain containing 4, NLR family CARD domain containing 4
External IDs	OMIM: 606831; MGI: 3036243; HomoloGene: 10924; GeneCards: NLRC4; OMA:NLRC4 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p22.3 Start 32,224,453 bp[1] End 32,265,732 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 E2 Start 74,732,433 bp[2] End 74,766,137 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte blood granulocyte gonad trabecular bone testicle bone marrow bone marrow cells spleen appendix Top expressed in jejunum ileum zygote duodenum colon secondary oocyte primary oocyte proximal tubule spleen stomach More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding protein homodimerization activity ubiquitin-protein transferase activity protein binding ATP binding magnesium ion binding cysteine-type endopeptidase inhibitor activity involved in apoptotic process identical protein binding Cellular component cytoplasm cytosol intracellular anatomical structure IPAF inflammasome complex nucleus Biological process pyroptosis inhibition of cysteine-type endopeptidase activity involved in apoptotic process immune system process regulation of cysteine-type endopeptidase activity involved in apoptotic process mitotic spindle assembly regulation of signal transduction defense response to bacterium positive regulation of NF-kappaB transcription factor activity detection of bacterium activation of innate immune response positive regulation of apoptotic process inflammatory response protein homooligomerization activation of cysteine-type endopeptidase activity involved in apoptotic process apoptotic process protein ubiquitination regulation of apoptotic process innate immune response Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 58484 268973 Ensembl ENSG00000091106 ENSMUSG00000039193 UniProt Q9NPP4 Q3UP24 RefSeq (mRNA) NM_001199138 NM_001199139 NM_001302504 NM_021209 NM_001033367 RefSeq (protein) NP_001186067 NP_001186068 NP_001289433 NP_067032 NP_001028539 Location (UCSC) Chr 2: 32.22 – 32.27 Mb Chr 17: 74.73 – 74.77 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

The NLRC4 protein is highly conserved across mammalian species. It bears homology to the C. elegans Ced4 protein. It contains an N-terminal CARD domain, a central nucleotide binding/NACHT domain, and a C-terminal leucine rich repeat (LRR) domain. It belongs to a family of NLR proteins that includes the transcriptional co-activator CIITA and the canonical inflammasome protein NLRP3. A truncated murine NLRC4 was the first member of this family whose crystal structure was solved.^[7]

Function

NLRC4 is best associated with triggering formation of the inflammasome. Unlike NLRP3, certain inflammasome-dependent functions of NLRC4 may be carried out independently of the inflammasome scaffold ASC. Human Ced4 homologs include APAF1, NOD1 (CARD4), and NOD2 (CARD15). These proteins have at least 1 N-terminal CARD domain followed by a centrally located nucleotide-binding domain (NBD or NACHT) and a C-terminal regulatory domain, found only in mammals, that contains either WD40 repeats or leucine-rich repeats (LRRs). CARD12 is a member of the Ced4 family and can induce apoptosis.^[6]

Interactions

NLRC4 has been shown to interact with NAIP (there is one human NAIP but mice express at least 4 distinct NAIP proteins). The NAIP/NLRC4 interaction may determine the ligand specificity.^[8] NLRC4-dependent inflammasome activity activates CASP1.^[9] Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.^[10]

Clinical significance

Humans bearing activating mutations in NLRC4 can develop an autoinflammatory syndrome characterized by acute fever, hepatitis, very high serum ferritin, and other features suggestive of Macrophage Activation Syndrome (MAS). Some patients also developed a potentially life-threatening enterocolitis that abated during early childhood.^[11][12] In these patients, chronic and extraordinary elevation of serum IL-18 is found, in distinction from patients with NLRP3 mutations who develop Cryopyrin Associated Periodic Syndromes.^[11] A large Japanese family had much milder disease associated with cold-induced urticaria that was caused by a dominantly inherited NLRC4 mutation.^[13]

References

1. GRCh38: Ensembl release 89: ENSG00000091106 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000039193 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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 (Jun 2001). "Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis". Biochemical and Biophysical Research Communications. 284 (1): 77–82. doi:10.1006/bbrc.2001.4928. PMID 11374873.
6. "Entrez Gene: NLRC4 NLR family, CARD domain containing 4".
7. Hu Z, Yan C, Liu P, Huang Z, Ma R, Zhang C, Wang R, Zhang Y, Martinon F, Miao D, Deng H, Wang J, Chang J, Chai J (Jul 2013). "Crystal structure of NLRC4 reveals its autoinhibition mechanism". Science. 341 (6142): 172–5. Bibcode:2013Sci...341..172H. doi:10.1126/science.1236381. PMID 23765277. S2CID 12360722.
8. Kofoed EM, Vance RE (Sep 2011). "Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity". Nature. 477 (7366): 592–5. Bibcode:2011Natur.477..592K. doi:10.1038/nature10394. PMC 3184209. PMID 21874021.
9. Damiano JS, Oliveira V, Welsh K, Reed JC (Jul 2004). "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses". The Biochemical Journal. 381 (Pt 1): 213–9. doi:10.1042/BJ20031506. PMC 1133779. PMID 15107016.
10. Man SM, Hopkins LJ, Nugent E, Cox S, Glück IM, Tourlomousis P, Wright JA, Cicuta P, Monie TP, Bryant CE (May 2014). "Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 111 (20): 7403–8. Bibcode:2014PNAS..111.7403M. doi:10.1073/pnas.1402911111. PMC 4034195. PMID 24803432.
11. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, Chapelle D, Plass N, Huang Y, Villarino AV, Biancotto A, Fleisher TA, Duncan JA, O'Shea JJ, Benseler S, Grom A, Deng Z, Laxer RM, Goldbach-Mansky R (Oct 2014). "An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome". Nature Genetics. 46 (10): 1140–6. doi:10.1038/ng.3089. PMC 4177369. PMID 25217959.
12. Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP (Oct 2014). "Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation". Nature Genetics. 46 (10): 1135–9. doi:10.1038/ng.3066. PMC 4177367. PMID 25217960.
13. Kitamura A, Sasaki Y, Abe T, Kano H, Yasutomo K (Nov 2014). "An inherited mutation in NLRC4 causes autoinflammation in human and mice". The Journal of Experimental Medicine. 211 (12): 2385–96. doi:10.1084/jem.20141091. PMC 4235634. PMID 25385754.

Further reading

• Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES (Jul 2001). "Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1". The Journal of Biological Chemistry. 276 (30): 28309–13. doi:10.1074/jbc.C100250200. PMID 11390368.
• Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC (Jul 2001). "CLAN, a novel human CED-4-like gene". Genomics. 75 (1–3): 77–83. doi:10.1006/geno.2001.6579. PMID 11472070.
• Fu WN, Bertoni F, Kelsey SM, McElwaine SM, Cotter FE, Newland AC, Jia L (Jan 2003). "Role of DNA methylation in the suppression of Apaf-1 protein in human leukaemia". Oncogene. 22 (3): 451–5. doi:10.1038/sj.onc.1206147. PMID 12545166.
• Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J (Mar 2004). "NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder". Immunity. 20 (3): 319–25. doi:10.1016/S1074-7613(04)00046-9. PMID 15030775.
• Damiano JS, Oliveira V, Welsh K, Reed JC (Jul 2004). "Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses". The Biochemical Journal. 381 (Pt 1): 213–9. doi:10.1042/BJ20031506. PMC 1133779. PMID 15107016.
• Damiano JS, Newman RM, Reed JC (Nov 2004). "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". Journal of Immunology. 173 (10): 6338–45. doi:10.4049/jimmunol.173.10.6338. PMID 15528373.
• Sadasivam S, Gupta S, Radha V, Batta K, Kundu TK, Swarup G (Jan 2005). "Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis". Oncogene. 24 (4): 627–36. doi:10.1038/sj.onc.1208201. PMID 15580302.
• Lu C, Wang A, Wang L, Dorsch M, Ocain TD, Xu Y (Jun 2005). "Nucleotide binding to CARD12 and its role in CARD12-mediated caspase-1 activation". Biochemical and Biophysical Research Communications. 331 (4): 1114–9. doi:10.1016/j.bbrc.2005.04.027. PMID 15882992.
• Thalappilly S, Sadasivam S, Radha V, Swarup G (Jun 2006). "Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis". The FEBS Journal. 273 (12): 2766–78. doi:10.1111/j.1742-4658.2006.05293.x. PMID 16817903. S2CID 21214841.