Rather than revealing a role in ER stress-induced apoptosis 28, genetic and functional studies check details of human caspase-12 suggested its involvement in regulating caspase-1-mediated inflammatory processes 29. Caspase-12 is expressed in all mammals tested to date, but has acquired deleterious mutations in humans 30. Most notably, a SNP (C125GATGA) introduces a premature stop codon in exon 4 of the gene in the majority of the human population (null allele), which leads to the production of an unstable RNA product 29, 31. However,
in individuals of African descent or from South-East Asia and Central and South America, the ancestral allele encodes an arginine at this position allowing for the expression of a full-length protein (caspase-12L). Caspase-12L antagonizes the inflammasome and NF-κB signaling and is associated with a blunted cytokine response and enhanced susceptibility to bacterial sepsis 29. Population genetic studies have indicated that the caspase-12 null allele, which provides relative resistance to sepsis, was driven to near fixation in the human genome ∼60 000 years ago due to positive
Selleck PCI-32765 selection (i.e. rising infectious diseases and sepsis in Europe and Asia) 32, 33. Consistent with the role of human caspase-12 in sepsis, caspase-12-deficient mice clear bacterial infection more efficiently than WT mice, have enhanced production of IL-1β and IL-18, and resist polymicrobial sepsis-related mortality 34. Caspase-12 has therefore been proposed to be a decoy caspase that blocks caspase-1 activation, plausibly in a manner similar to how the decoy caspase-8-like protein cFLIP regulates apoptosis. Leblanc et al. have recently reported that, by binding to RIP2, caspase-12 displaces TRAF6 from the NOD complex, leading to inhibition of NOD signaling 35. As NOD2 is mutated in the inflammatory
Etoposide molecular weight bowel disorder CD (see below), it is tempting to speculate that caspase-12 might have a modifier effect in this condition. The potential of GWAS to uncover genetic risk factors with intermediate effect in complex disease has been widely debated 36. In the case of CD, decades of research effort have identified two uniformly replicated genetic risk factors (CARD15 which encodes NOD2 and the IBD5 haplotype) 37. GWAS have since identified more than 30 susceptibility loci for CD 38. However, despite this recent progress, the proportion of heritability explained by these CD-associated loci is not more than 20%. Interestingly, the locus most robustly associated with CD by GWAS is the first gene identified by genome-wide linkage studies at the end of the 1990s, CARD1539. Through homotypic CARD interactions, NOD2 interacts with RIP2 to activate NF-κB and MAP kinase signalling. Like NLRP3, NOD2 has an NBD with ATP-binding activity, and ten C-terminal leucine-rich repeats (LRR) through which it recognizes bacterial peptidoglycans, particularly mycobacterial N-glycolyl muramyl dipeptide 40.