Does a caspase also play a role in mitochondrial turnover?
As mentioned above, the cell line L929.hCD95 can be killed either necrotically by treatment with TNF, or apoptotically by addition of CD95L, and this pathway is blocked by zVAD-fmk. So, what happens when a caspase inhibitor is added to TNF-treated L929 cells? This provided the second surprise. Not only did the caspase inhibitor zVAD-fmk, as expected, not block the TNF-triggered necrotic pathway, but unexpectedly it dramatically synergized (Vercammen et al., 1998a)! In the presence of the inhibitor, the cells became at least 1000-fold more sensitive to TNF. This corresponded to an enhanced ROS production. A similar sensitization was obtained by constitutive expression of CrmA (CrmA is a cowpox virus-derived gene; CrmA protein inhibits efficiently caspase-8 and -1, but not effector caspases; Zhou et al., 1997). An inactive mutant of CrmA (T291R) did not synergize (G Van Loo, 1999 unpublished results). These results suggest that a caspase, most probably caspase-8, or another protease simi
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