02 BOOK OF ABSTRACTS .indd

Involvement of cysteine cathepsins in apoptosis
Lea Boji~ 1 , Ana Petelin 1 , Gabriela Droga Mazovec 1 , Rok Romih 2 ,
Veronika Stoka 1 , Vito Turk 1 and Boris Turk 1
1
Department of Biochemistry and Molecular Biology, Jo`ef Stefan Institute, Ljubljana,
Slovenia; 2 Institute for Cells Biology, Medicine Faculty, Ljubljana, Slovenia
Cysteine cathepsins have long been thought to be involved primarily in the
non-selective degradation of proteins inside lysosomal compartments, where
acidic pH facilitates their optimal activity (Turk et al., 2001). Nevertheless, there
is accumulating evidence for their specific non-redundant in vivo functions of
papain-like cathepsins. In certain tissues and cell types these peptidases have been
localized outside lysosomes and it was suggested that they preserve some residual
proteolytic activity at neutral pH. This enables them to act as a signaling molecules
in a variety of processes. Recently, we showed that lysosomal cathepsins B, L, S,
K and H cleaved and activated the proapoptotic BH3-only Bcl-2 homologue Bid
(Cirman et al., 2004) both in vitro and in HeLa cellular model following lysosomal
disruption by the lysosomotropic agent LeuLeuOMe. Using LeuLeuOMe we found
that lysosomal disruption, followed by translocation of lysosomal peptidases into
the cytosol and subsequent cleavage of Bid, caused mitochondrial destabilization
and fragmentation of cristae. Moreover, in HaCaT cell line, Bcl-XL was found to be
degraded with cysteine cathepsins and degaradation could be blocked by a general
inhibitor of papain-like peptidases E-64d, but not by caspase inhibitor z-VAD-fmk.
Therefore, we suggest that cysteine cathepsins with the assistance of different Bcl-
2 family members play a major role during apoptosis after lysosomal membrane
permeabilization.
Turk, V., Turk, B., Turk, D. (2001) EMBO J 20, 4629-4633
74p3
Cirman, T., Ore{i}, K., Droga-Mazovec, G., Turk, V., Reed, J., Myers,
R., Salvesen, G., Turk, B. (2004) J Biol Chem 279, 5, 3578-3587