The NLRC4 protein is highly conserved across mammalian species. It bears homology to theC. elegans Ced4 protein. It contains an N-terminalCARD 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-activatorCIITA and the canonical inflammasome proteinNLRP3. A truncated murine NLRC4 was the first member of this family whose crystal structure was solved.[7]
NLRC4 is best associated with triggering formation of theinflammasome. Unlike NLRP3, certain inflammasome-dependent functions of NLRC4 may be carried out independently of the inflammasome scaffoldASC. Human Ced4 homologs includeAPAF1,NOD1 (CARD4), andNOD2 (CARD15). These proteins have at least 1N-terminal CARD domain followed by a centrally located nucleotide-binding domain (NBD or NACHT) and aC-terminal regulatory domain, found only in mammals, that contains eitherWD40 repeats orleucine-rich repeats (LRRs). CARD12 is a member of the Ced4 family and can induceapoptosis.[6]
NLRC4 has been shown tointeract 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 activatesCASP1.[9] Under certain circumstances, NLRC4 and NLRP3 may occupy the same inflammasome complex.[10]
Humans bearing activating mutations in NLRC4 can develop anautoinflammatory syndrome characterized by acute fever, hepatitis, very high serum ferritin, and other features suggestive ofMacrophage 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 serumIL-18 is found, in distinction from patients with NLRP3 mutations who developCryopyrin 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]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.PMID11374873.
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.PMID11472070.
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.PMID15882992.
