Figure 11.

Compartmentalization of TNF-R1 signalling and A-SMase activation. Binding of TNF ligand to TNF-R1 initializes the clathrin-dependent endocytosis and the recruitment of adaptor proteins TRADD, FADD and caspase-8. Within the receptosome-bound death-inducing signalling complex (DISC), caspase-8 is activated. Along the endocytotic pathway, TNF receptosomes fuse with trans-Golgi vesicles containing pro-acid sphingomyelinase (pro-A-SMase) and pre-pro-cathepsin D (pre-pro-CTSD) to form multivesicular organelles. There, activation of caspase-7 by active caspase-8 leads to the cleavage and activation of pro-A-SMase. Activated A-SMase generates ceramide, which activates CTSD and mediates its translocation from the late endosome to the cytosol. In this compartment, the proapoptotic protein Bid is cleaved by CTSD to tBid resulting in release of cytochrome C from mitochondria and activation of caspase-9 and caspase-3 leading to apoptotic cell death.