Alt. symbols: CARD12 | CLAN1 | ipaf | CLACLANB | CLANC | CLAND | CLR2.1 | CLAN

Approved name: NLR family CARD domain containing 4
Alt. names: caspase recruitment domain family, member 12 | nucleotide-binding oligomerization domain, leucine rich repeat and CARD domain containing 4, NOD-like receptor C4

Location: 2p22.3: 32224453 - 32265732 (-)
Gene type: protein_coding, 5 transcripts.

Scores: LoFtool: 0.850000 | pLI: 0.00000004 | LOEUF: 0.918

HGNC: 16412

NCBI: 58484, RefSeq: NG_041780.1

Ensembl: ENSG00000091106.19

LRG_1317 | Status: public

OMIM: 606831

Expression | ProteinAtlas

Like other NLRs, NLRC4 play essential roles in innate immune response by indirectly sensing specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis (PMID: 15107016). Unlike other NLRs, NLRC4 does not directly recognize bacterial ligands but rather co-assembles with the NAIP receptor to form a functional inflammasome that acts as a cytosolic sensor of Gram-negative bacteria in innate immune and intestinal epithelial cells (PMID: 29247997). Unlike other inflammasomes, the NLRC4 inflammasome contains an N-terminal CARD instead of pyrin domain and can activate caspase-1 independently of ASC (PMID: 11390368). But like other inflammasomes, activated NLRC4 can use both pro-inflammatory cytokine (IL-1β and IL-18) production and pyroptosis to help epithelial cells eliminate harmful bacteria (PMID: 33494299).

Monoallelic NLRC4 GOF mutations are associated with a spectrum of autoinflammatory phenotypes ranging from milder Familial cold autoinflammatory syndrome (FCAS4) [OMIM: 616115] to severe life-threatening Autoinflammation with infantile enterocolitis (AIFEC) [OMIM: 616050] or macrophage-activation syndrome (MAS) (PMID: 25217959, 25217960). FCAS4 is a rare autoinflammatory disease characterized by recurrent episodes of maculopapular rash associated with arthralgias, myalgias, fever and chills, s welling of the extremities, and conjunctivitis after generalized exposure to cold. FCAS-associated NLRC4 variants reside in the winged helix domain (WHD) of the NACHT domain. Like for CAPS patients with NLRP3 mutations, NLRC4 mutations lead to enhanced inflammasome activity but only those affecting highly conserved motifs spontaneously activate the protein, while milder mutations reduce the threshold for inflammasome activation (PMID: 34035534). But unlike CAPS patients, NLRC4 patients show a chronic and significant elevation of serum IL-18, explaining why those with NLRC4-MAS respond well to blockade with IL-18 binding protein (PMID: 27876626). AIFEC is characterized by neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of MAS. Affected individuals tend to have poor overall growth and GI symptoms in infancy, recurrent febrile episodes with splenomegaly, and sometimes hematologic disturbances, arthralgias, or myalgias. Some MAS-associated mutations are found in the highly conserved HD1 subdomain of NACHT and lead to constitutive protein activation, while others located near the ATP-binding pocket result in highly active protein. A third group of more C-terminal mutations are thought to increase protein activation by creating an LRR–LRR interface important for NLRC4 oligomerization (PMID: 29778503, 31870725). Recently, a novel GOF variant (W655S) has been reported in the literature in association with the SLE and MAS phenotype of a woman and her son (PMID:37567492). [Load More]