Population genetics and biochemical characterization of human caspase-12 (100.16)

Abstract Casp12 encodes the protein caspase 12 (casp12), which has a downregulatory effect upon IL-1 activation and subsequent inflammatory immune reactions. Casp12 is primarily a pseudogene (Casp12p1) in most humans, but ~20% of people of African ancestry have a functional, intact form of Casp12. This allele is increased in African-American individuals with severe sepsis. We examined Casp12 allele distribution in populations of Indians and Central Asians and in a pilot screen found that a small number of Tamils (2 of 10; 20%) possess the intact Casp12 allele. Gujratis, Punjabis and other Central Asians (Baluchi, Iranian, Pakistani or Afghani) were all homozygous for Casp12p1, as were nearly all other Indians (18/19; 95%). Thus, small but distinct populations outside of Africa still harbor Casp12. To examine the biochemical properties of the protein, we expressed recombinant human casp12. By fractionation techniques, casp12 was found exclusively in the cytosol. In order to better characterize the role of casp12 in the inflammatory process, we generated a rabbit polyclonal antiserum to casp12 and used it to determine if the protein interacted directly with components of the inflammasome. Immunoprecipitation of casp12 revealed that the protein did not interact with ASC, Cardinal, or Caspase 5. Casp12 may thus exert its downregulatory effects by direct interaction with IL1.