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Gene Review

NLRC4  -  NLR family, CARD domain containing 4

Homo sapiens

Synonyms: AIFEC, CARD, LRR, and NACHT-containing protein, CARD12, CLAN, CLAN1, ...
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High impact information on NLRC4

  • Identification and analysis of Clan CA (papain) cysteine proteases in primitive protozoa and metazoa have suggested that this enzyme family is more diverse and biologically important than originally thought [1].
  • A constitutively active Ipaf lacking its COOH-terminal LRR domain can induce autocatalytic processing and activation of procaspase-1 and caspase-1-dependent apoptosis in transfected cells [2].
  • Here we describe the identification of a human Apaf-1-related protein, named Ipaf that contains an NH2-terminal CARD domain, a central nucleotide-binding domain, and a COOH-terminal regulatory leucine-rich repeat domain (LRR) [2].
  • Our results show that p53 can directly induce Ipaf gene transcription, which contributes to p53-dependent apoptosis in at least some human cells [3].
  • Doxorubicin-induced apoptosis was also inhibited by Ipaf-directed small hairpin RNA [3].

Biological context of NLRC4


Anatomical context of NLRC4

  • Expression of caspase 1 with activated Ipaf resulted in the activation of Bax at mitochondria [7].
  • Mitochondrial membrane permeabilization was induced by caspase 1 and activated Ipaf, which was inhibited by Bcl2, but not by caspase 9s [7].
  • Thus, Ipaf may contribute to modulate the response of myeloid cells to genotoxic and pro-inflammatory stimuli [5].
  • Here, we describe that Ipaf is highly expressed in myelomonocytic cells and that the mRNA levels of Ipaf progressively increase during differentiation of CD34(+) progenitors to granulocytes and monocytes [5].

Associations of NLRC4 with chemical compounds

  • Through the application of sequence search algorithms capable of detecting distant homologies, work we reported briefly before but not in its entirety, it has been determined that the N-terminal half of AtPCS1 and its equivalents from other sources have the hallmarks of a papain-like, Clan CA Cys protease [8].

Physical interactions of NLRC4

  • The CARD domain of CARD12 interacts selectively with the CARD domain of ASC, a recently identified proapoptotic protein [4].
  • A functional p53-binding site was identified in the Ipaf promoter [3].

Regulatory relationships of NLRC4


Other interactions of NLRC4

  • CARD12 is most similar in structure to the CED4/Apaf-1 family member CARD4, and is comprised of an N-terminal caspase recruitment domain (CARD), a central nucleotide-binding site (NBS), and a C-terminal domain of leucine-rich repeats (LRR) [4].
  • Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53 [3].


  1. A cathepsin B-like protease is required for host protein degradation in Trypanosoma brucei. Mackey, Z.B., O'Brien, T.C., Greenbaum, D.C., Blank, R.B., McKerrow, J.H. J. Biol. Chem. (2004) [Pubmed]
  2. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. Poyet, J.L., Srinivasula, S.M., Tnani, M., Razmara, M., Fernandes-Alnemri, T., Alnemri, E.S. J. Biol. Chem. (2001) [Pubmed]
  3. Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis. Sadasivam, S., Gupta, S., Radha, V., Batta, K., Kundu, T.K., Swarup, G. Oncogene (2005) [Pubmed]
  4. Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Geddes, B.J., Wang, L., Huang, W.J., Lavellee, M., Manji, G.A., Brown, M., Jurman, M., Cao, J., Morgenstern, J., Merriam, S., Glucksmann, M.A., DiStefano, P.S., Bertin, J. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  5. Ipaf is upregulated by tumor necrosis factor-alpha in human leukemia cells. Gutierrez, O., Pipaon, C., Fernandez-Luna, J.L. FEBS Lett. (2004) [Pubmed]
  6. Characteristics of traditional birth attendants and their beliefs and practices in the Offot Clan, Nigeria. Itina, S.M. Bull. World Health Organ. (1997) [Pubmed]
  7. Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis. Thalappilly, S., Sadasivam, S., Radha, V., Swarup, G. FEBS J. (2006) [Pubmed]
  8. Mutagenic definition of a papain-like catalytic triad, sufficiency of the N-terminal domain for single-site core catalytic enzyme acylation, and C-terminal domain for augmentative metal activation of a eukaryotic phytochelatin synthase. Romanyuk, N.D., Rigden, D.J., Vatamaniuk, O.K., Lang, A., Cahoon, R.E., Jez, J.M., Rea, P.A. Plant Physiol. (2006) [Pubmed]
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