Subcellular compartmentalization of TNF receptor-1 and CD95 signaling pathways

Receptors that belong to the family of death-receptors including TNF receptor-1 (TNF-R1), CD95 (Fas, APO-1) and TRAIL receptors (TRAIL-R1, TRAIL R2/DR4/DR5) transduce signals resulting in entirely different biological outcomes: They promote cell death via apoptosis but are also capable of inducing anti-apoptotic signals through the transcription factor nuclear factor NF-κB or activation of the proliferative MAPK/ERK protein kinase cascade resulting in cell protection and tissue regeneration. Recent findings revealed a regulatory role of receptor internalization and its intracellular trafficking in selectively transmitting signals that lead either to apoptosis or to the survival of the cell, providing a clue to the understanding of these contradictory biological phenomena.In this chapter we review our data obtained during the Collaborative Research Center 415 (CRC 415) focusing on the compartmentalization of TNF-R1 and CD95 pro and anti-apoptotic signaling. We will address the role of internalization in determining the fate of the receptors. We suggest that fusion of internalized TNF-receptosomes with trans-Golgi vesicles is a novel mechanism to transduce death signals along the endosomal trafficking route. The roles of acid sphingomyelinase, the lipid second messenger ceramide, and the aspartate-protease cathepsin D as novel players in the cell death scenario is also highlighted. We report on the regulation of NF-κB signaling by recruitment of the endosomal E3-ubiquitin ligases CARP-2 and CARP-1 during TNF-receptosome trafficking. The biological significance of TNF receptor-1 compartmentalization is demonstrated by the strategy of adenoviruses to impede TNF-R1 internalization and by this preventing host cell apoptosis.