Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8.

Caspase-8 is believed to play an obligatory role in apoptosis initiation by death receptors, but the role of its structural relative, caspase-10, rema ins controversial. Although earlier evidence implicated caspase-10 in apopt osis signaling by CD95L and Apo2L/TRAIL, recent studies indicated that thes e death receptor ligands recruit caspase-8 but not caspase-10 to their deat h-inducing signaling complex (DISC) even in presence of abundant caspase-10 . We characterized a series of caspase-10-specific antibodies and found tha t certain commercially available antibodies cross-react with HSP60, sheddin g new light on previous results. The majority of 55 lung and breast carcino ma cell lines expressed mRNA for both caspase-8 and -10; however, immunoblo t analysis revealed that caspase-10 protein expression was more frequently absent than that of caspase-8, suggesting a possible selective pressure aga inst caspase-10 production in cancer cells. In nontransfected cells express ing both caspases, CD95L and Apo2L/TRAIL recruited endogenous caspase-10 as well as caspase-8 to their DISC, where both enzymes were proteolytically p rocessed with similar kinetics. Caspase-10 recruitment required the adaptor FADD/ Mort1, and caspase-10 cleavage in vitro required DISC assembly, cons istent with the processing of an apoptosis initiator. Cells expressing only one of the caspases underwent ligand-induced apoptosis, indicating that ea ch caspase can initiate apoptosis independently of the other. Thus, apoptos is signaling by death receptors involves not only caspase-8 but also caspas e-10, and both caspases may have equally important roles in apoptosis initi ation.