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NLR family, CARD domain containing 4
External IDs OMIM606831 MGI3036243 HomoloGene10924 GeneCards: NLRC4 Gene
Species Human Mouse
Entrez 58484 268973
Ensembl ENSG00000091106 ENSMUSG00000039193
UniProt Q9NPP4 Q3UP24
RefSeq (mRNA) NM_001199138 NM_001033367
RefSeq (protein) NP_001186067 NP_001028539
Location (UCSC) Chr 2:
32.22 – 32.27 Mb
Chr 17:
74.43 – 74.46 Mb
PubMed search [1] [2]

NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.[1][2]


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.[3]


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.[2]


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.[4] NLRC4-dependent inflammasome activity activates CASP1.[5] Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.[6]

Clinical significance[edit]

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.[7][8] 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.[7] A large Japanese family had much milder disease associated with cold-induced urticaria that was caused by a dominantly inherited NLRC4 mutation.[9]


  1. ^ 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. 
  2. ^ a b "Entrez Gene: NLRC4 NLR family, CARD domain containing 4". 
  3. ^ 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. 
  4. ^ 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 3184209. PMID 21874021. 
  5. ^ 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. 
  6. ^ 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 4034195. PMID 24803432. 
  7. ^ a b 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. 
  8. ^ 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. 
  9. ^ 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[edit]