Compartmentalization of TNF-Receptor 1 Signaling: TNF-R1-Associated Caspase-8 Mediates Activation of Acid Sphingomyelinase in Late Endosomes

Tumor necrosis factor-α (TNF-α) is known as a highly pleiotropic cytokine. Stimulation of TNF-receptor 1 (TNF-R1) by TNF-α elicits the transduction of intracellular signals that on the one side promote cell death by apoptosis. However, TNF-R1 may also transduce non-apoptotic signals that lead to inflammatory responses through the activation of the transcription factor nuclear factor-κB (NF-κB) or to cell proliferation through activation of the mitogen-activated protein kinase (MAPK) cascade. A clue to the understanding of these contradictory biological phenomena may arise from recent findings which reveal a regulatory role of receptor endocytosis and intracellular receptor trafficking in selective transmission of signals, which either promote apoptosis or rather cell survival. Although internalization of cell surface receptors has traditionally been regarded as a means to shut down signaling via receptor degradation, there is now good evidence for an active role of many internalized surface receptors in the continuation of signal transmission along the endocytic pathway. Thus endocytosis may control the quality, intensity, duration, and spatial distribution of signaling events. TNF-induced apoptotic signals lead to an enhanced generation of ceramide by the enzyme sphingomyelin phosphodiesterase 1 (SMPD1, also known as acid sphingomyelinase [A-SMase]). Since TNF-triggered activation of A-SMase is linked to the death domain of TNF-receptor 1 (TNF-R1) and since the death domain adapter proteins FADD and caspase-8 are recruited during internalization of TNF-R1 to endosomes (TNF-receptosomes), we examined the possibility that A-SMase could be activated by caspase-8 within this compartment. Since we observed TNF-induced proteolytic processing and activation of pro-A-SMase that depended on the presence of caspase-8, we propose that activation of A-SMase within TNF-receptosomes requires activation of caspase-8 and probably further downstream proteases. Thus the fusion of internalized TNF-receptosomes with trans-Golgi vesicles containing the proform of A-SMase should be recognized as a novel mechanism to transduce death signals along the endocytic route.