Atractyloside‐induced release of cathepsin B, a protease with caspase‐processing activity

Abstract

Recent data show that a strong relation exists in certain cells between mitochondria and caspase activation in apoptosis. We further investigated this relation and tested whether treatment with the permeability transition (PT)-inducing agent atractyloside of Percoll-purified mitochondria released a caspase-processing activity. Following detection of procaspase-11 processing, we further purified this caspase-processing protease and identified it as cathepsin B. The purified cathepsin B, however, was found to be derived from lysosomes which were present as minor contaminants in the mitochondrial preparation. Besides procaspase-11, caspase-1 is also readily processed by cathepsin B. Procaspase-2, -6, -7, -14 are weak substrates and procaspase-3 is a very poor substrate, while procaspase-12 is no substrate at all for cathepsin B. In addition, cathepsin B induces nuclear apoptosis in digitonin-permeabilized cells as well as in isolated nuclei. All newly described activities of cathepsin B, namely processing of caspase zymogens and induction of nuclear apoptosis, are inhibited by the synthetic peptide caspase inhibitors z-VAD.fmk, z-DEVD.fmk and to a lesser extent by Ac-YVAD.cmk.z 1998 Federation of European Biochemical Societies.

The CEACAM1-mediated apoptosis pathway is activated by CEA and triggers dual cleavage of CEACAM1

“…Our experiments using specific protease inhibitors suggest the involvement of non-caspase proteases in CEACAM1-4L-induced apoptosis including aspartate proteases, metalloproteinases and cathepsin B. In fact, activation of caspase-1 by cathepsin B and inhibition of the corresponding apoptosis pathway by the addition of Z-VAD.fmk have been well documented (Vancompernolle et al, 1998). It is thus likely that procaspase activation may be initiated by these proteases.…”

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

“…In particular, some forms of apoptosis can be inhibited by blocking cathepsin B. It is of interest that many peptide caspase inhibitors are also capable of blocking cathepsin B activity both in vitro and in cells [36,37]. Furthermore, cathepsin B has been shown to process caspase 3 under neutral conditions, albeit weakly [37].…”

Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1)

“…24 Alternatively, cathepsins could cleave and activate caspases or their downstream death effector substrates, 25 thereby causing apoptosis. In support of the former mechanism, it has been shown that cathepsin B can activate the inflammatory caspases 1 and 11, 17,26 and that cathepsin L may activate caspase-3. 20 The final possible mode of cathepsin action places cathepsins far upstream in the apoptotic cascade, cleaving the proapoptotic Bcl-2 family member Bid to initiate mitochondrial release of cytochrome c. This last hypothesis received in vitro confirmation when it was shown that lysosomal extracts containing cathepsins were able to cleave purified Bid in a physiologically relevant manner that supported apoptosis.…”

“…[3][4][5][6][7][8][9][10][11][12][13][14] Although cathepsins normally reside in the lysosome and carry out nonselective degradation of proteins, a strong case was made for the involvement of these proteases in apoptosis when it was shown that agents that disrupted lysosomes and caused cathepsins to redistribute to the cytoplasm inevitably resulted in apoptosis. 13,[15][16][17][18][19] Similarly, cathepsin inhibitor treatment blocked this apoptosis. 11,14,[18][19][20][21][22] Theoretically, the cathepsin proteases could induce apoptosis by a variety of different mechanisms.…”