The CASBAH: a searchable database of caspase substrates

Abstract

Apoptosis is coordinated by members of the caspase family of aspartic acid-specific proteases. Other members of this protease family also play essential roles in inflammation where they participate in the maturation of pro-inflammatory cytokines. To date, almost 400 substrates for the apoptosis-associated caspases have been reported and there are likely to be hundreds more yet to be discovered. Thus, the fraction of the proteome that is degraded (the degradome) by caspases during the demolition phase of apoptosis appears to be quite substantial. Despite this, we still know surprisingly little concerning how caspases provoke some of the signature events in apoptosis, such as membrane phosphatidylserine externalization, cellular retraction, chromatin condensation and apoptotic body production. The inflammatory caspases appear to be much more specific proteases than those involved in apoptosis and only two confirmed substrates for these proteases have been described to date. Here, we have compiled a comprehensive list of caspase substrates and describe a searchable web resource (The Casbah; www.casbah.ie) which contains information pertaining to all currently known caspase substrates. We also discuss some of the unresolved issues relating to caspase-dependent events in apoptosis and inflammation.

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

“…Most caspase targets lose function when they are cleaved during apoptosis (Lamkanfi et al, 2007), although a small number of proteins acquire a new function after cleavage (Luthi and Martin, 2007). For example, cleavage of the BH3-only protein Bid by caspase-8 results in its acquisition of a proapoptotic function (Luo et al, 1998).…”

Apoptosis and autophagy: regulatory connections between two supposedly different processes

“…Morphological changes and death in apoptotic cells are caused by caspases, which cleave about 400 proteins (24). Apoptotic caspases include "initiator caspases" (caspase-2, −8, −9 and −10) that start an apoptotic cascade and "effector caspases" (caspase-3, −6 and −7) that disassemble the cell.…”

“…One example of autophagic cell death was caused by increased reactive oxygen species resulting from autophagic degradation of catalase (23). Unlike apoptosis, which relies upon the activation of caspases that cleave hundreds of target proteins (24), autophagic cell death is usually thought of as caspase-independent (21). Indeed, two of the best examples of autophagic cell death where the demise of the cell was shown to require the autophagy machinery took place in cells with profound defects in the apoptosis machinery (25) or in the presence of caspase inhibitors (26).…”

“…Indeed, two of the best examples of autophagic cell death where the demise of the cell was shown to require the autophagy machinery took place in cells with profound defects in the apoptosis machinery (25) or in the presence of caspase inhibitors (26). Cells undergoing autophagic cell death or apoptosis look different (27); the characteristic cellular morphology associated with apoptosis is usually due to caspase cleavage of cytoskeletal and other structural proteins (24) so that apoptotic cells show early degradation of the cytoskeleton but preserve organelles until fairly late in the process. In contrast, autophagic cell death is associated with accumulation of large numbers of autophagic vesicles, which degrade organelles early in the process while the cytoskeleton remains intact and functional until late in the process (5).…”

Mitochondrial fission/fusion dynamics and apoptosis

“…These, in turn, cleave hundreds of substrates, a small subset of which is responsible for the morphological alterations to the cell architecture that is characteristic of apoptosis (Fischer et al, 2003;Luthi and Martin, 2007). The granzyme B pathway to caspase activation is initiated by cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to eliminate virally…”