Caspase-8 (MEROPS identifier C14.009) is a cytoplasmic cysteine endopeptidase with a preference for aspartyl bonds, acing at neutral pH []. It is active as a homodimer or as a heterodimer in association with the long isoform of FLICE, and proteolytic processing of the caspase-8 precursor is required for stabilisation of the dimer [, , ]. It is one of the activator caspases. Caspase-8 has a strict requirement for Asp in P1, a preference for Glu in P3 and small residues in P1' []. The caspase-8 proenzyme has two N-terminal death effector domains which are removed upon activation along with a linker region between the large and small subunits of the C-terminal catalytic domain. The death inducing signalling complex, composed of a transmembrane death receptor and the adapter protein FADD assembles at the cell membrane following binding of a death ligand. Procaspase-8 is recruited to this complex, and becomes active by dimerisation. Active caspase-8 can then activate the executioner caspases -3 and -7 [].Caspase-8 cleaves RIPK1, which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response. In humans, non-cleavable RIPK1 leads to autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response [, ].
This domain is present in the N-terminal region of the ShET2 enterotoxin produced by Shigella flexneri () and Escherichia coli (). This protein was found to confer toxigenicity in Ussing chamber assays, and the N-terminal region was found to be important for its enterotoxic effect. The N-terminal domain is a cysteine-type peptidase with a Cys/His/Asp catalytic triad that cleaves within the receptor-interacting protein homotypic interaction motifs found within host adaptor proteins such as receptor-interacting serine/threonine protein kinases RIPK1 and RIPK3, TIR-domain-containing adapter-inducing interferon beta and Z-DNA-binding protein 1, inactivating them and thus inhibiting necroptosis and inflammatory signalling []. The toxin is injected into the host cell by the type III secretion system [].Most proteins containing this domain are annotated as putative enterotoxins, but one member () is a regulator of acetyl CoA synthetase, and another two members (and ) are annotated as ankyrin-like regulatory proteins and contain Ank repeats ().
