NLRC4

NLRC4
Available structures
PDBOrtholog search: PDBe RCSB
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 MGI: 3036243 HomoloGene: 10924 GeneCards: NLRC4
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_001186067.1
NP_001186068.1
NP_001289433.1
NP_067032.3

NP_001028539.1

Location (UCSC) Chr 2: 32.22 – 32.27 Mb Chr 17: 74.43 – 74.46 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.[3][4]

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.[5]

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.[4]

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.[6] NLRC4-dependent inflammasome activity activates CASP1.[7] Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.[8]

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.[9][10] 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.[9] A large Japanese family had much milder disease associated with cold-induced urticaria that was caused by a dominantly inherited NLRC4 mutation.[11]

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ 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.
  4. 1 2 "Entrez Gene: NLRC4 NLR family, CARD domain containing 4".
  5. ↑ 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. doi:10.1126/science.1236381. PMID 23765277.
  6. ↑ Kofoed EM, Vance RE (Sep 2011). "Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity". Nature. 477 (7366): 592–5. doi:10.1038/nature10394. PMC 3184209Freely accessible. PMID 21874021.
  7. ↑ 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 1133779Freely accessible. PMID 15107016.
  8. ↑ 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". Proceedings of the National Academy of Sciences of the United States of America. 111 (20): 7403–8. doi:10.1073/pnas.1402911111. PMC 4034195Freely accessible. PMID 24803432.
  9. 1 2 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 4177369Freely accessible. PMID 25217959.
  10. ↑ 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 4177367Freely accessible. PMID 25217960.
  11. ↑ 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 4235634Freely accessible. PMID 25385754.

Further reading

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