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

• A novel human member of this family, called CARD12, was identified that induces apoptosis when expressed in cells [4].
• Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels [3].
• Ipaf-directed small hairpin RNA downregulated p53-induced Ipaf gene expression and also reduced p53-induced apoptosis [3].
• Additionally, treatment with tumor necrosis factor-alpha and exposure to UV radiation induced the transcriptional activation of Ipaf in human leukemia HL-60 cells [5].
• Characteristics of traditional birth attendants and their beliefs and practices in the Offot Clan, Nigeria [6].

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

• An activated form of Ipaf induced caspase 1-dependent apoptosis that was inhibited by Bcl2 and also by a dominant inhibitor of caspase 9 (caspase 9s) [7].
• A dominant-negative mutant of Ipaf inhibited p53-induced and doxorubicin-induced apoptosis by about 50% [3].

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].

References