Caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase in TNF-R1 receptosomes.

摘要: We previously demonstrated that tumour necrosis factor (TNF)-induced ceramide production by endosomal acid sphingomyelinase (A-SMase) couples to apoptosis signalling via activation of cathepsin D and cleavage Bid, resulting in caspase-9 caspase-3 activation. The mechanism TNF-mediated A-SMase within the endolysosomal compartment is poorly defined. Here, we show TNF-induced depends on functional caspase-8 caspase-7 expression. active forms all three enzymes, caspase-8, A-SMase, but not caspase-3, colocalize internalized TNF receptosomes. While are unable induce purified pro-A-SMase, found mediates direct interaction proteolytic 72-kDa pro-A-SMase zymogen at non-canonical site after aspartate 253, generating an 57 kDa molecule. Caspase-7 down modulation revealed link between confirming as one further mode Our data suggest a cascade receptosomes involving sequential for induction pro-A-SMase.