Caspase-4 & caspase-5
Two caspases, originally designated ICErel-II (caspase-4) and ICErel-III (caspase-5), were cloned from human monocytic cells. Both were highly homologous to human caspase-1 (52% identical) and ced-3 (25% identical) and both contained the absolutely conserved pentapeptide sequence Gln-Ala-Cys-Arg-Asp containing the catalytic cysteine residue. Other structural motifs that were comparable with ICE suggest that ICErel-II and ICErel-III are also synthesised as larger proenzymes which are proteolyticaly processed to form heterodimeric active enzymes. Pro-IL1b processing activity could not be detected in cells transfected with ICErel- II or ICErel-III, but prodomainless truncated forms of ICErel- II and ICErel-III were capable of effectively inducing fibroblast apoptosis. ICErel-II and ICErel-III may, therefore, participate in proteolytic events culminating in the apoptotic death of human cells (Munday et al., 1995)
In parallel ICH-2, a novel human gene encoding a caspase, was identified. ICH-2 mRNA is widely expressed in human tissues in a pattern similar to, but distinct from, that of caspase-1. Overexpression of ICH-2 in insect cells induces apoptosis. Purified ICH-2 is functional as a protease in vitro. A comparison of the inhibitor profiles and substrate cleavage by ICH-2 and caspase-1 shows that the enzymes share catalytic properties but may differ in substrate specificity's, suggesting that the two enzymes have different functions in vivo (Kamens et al., 1995)
At the same time a cDNA encoding a protein named TX was cloned. This turned out to be identical to ICH-2, with more than 50% overall sequence identity with caspase-1 and approximately 30% sequence identity with the caspase-2 and ced-3. A computer homology model of TX was constructed based on the X-ray coordinates of the caspase-1 crystal recently published. This model suggests that TX is a cysteine protease, with the P1 aspartic acid substrate specificity retained. Transfection experiments demonstrated that TX is a protease which is able to cleave itself and the p30 caspase-1 precursor, but is not able to generate mature IL-1b from pro-IL-1b beta. In addition, TX induces apoptosis in transfected COS cells (Faucheu et al., 1995). Mouse caspase-11 is propably the homologue of human caspase-4.