Death ligands such as TRAIL and TNFα trigger apoptosis through the mitochondrial (type II) pathway, involving caspase-8-mediated cleavage of the proapoptotic substrate Bid, which induces mitochondrial-outer-membrane permeabilisation (MOMP). On page , Markus Rehm and colleagues now investigate the observation that Bid cleavage is temporally separated from caspase-8 activation, hinting that regulatory factors might control this step in the pathway. Previous population-based studies suggested that the protein kinase CK2 might play a regulatory role in the mitochondrial apoptotic pathway. Here, the authors use FRET and time-lapse imaging to analyse caspase-8-mediated substrate cleavage at the single-cell level, and show that inhibition of CK2 activity eliminates the lag time between TRAIL-induced caspase-8 activation and Bid cleavage, probably by modulating the phosphorylation status of CK2 substrates. The authors conclude that CK2 activity provides ‘transient tolerance’ to caspase-8 activity by delaying Bid cleavage. These data uncover an additional regulatory step in the mitochondrial apoptotic pathway and caution that the extent of Bid cleavage cannot be determined experimentally on the basis of caspase-8 activity.
