Updated project metadata. Apoptosis and autophagy are programs of controlled cellular suicide or survival, closely interconnected at multiple levels to ensure balanced answers to stress signals, and often dysregulated in cancer. Here, we identified FYCO1, a protein that promotes microtubule plus end–directed transport of autophagic and endosomal vesicles as molecular interaction partner of activated caspase 8. The absence of FYCO1 sensitized cells to basal and TRAIL induced apoptosis by receptor accumulation and stabilization of the Death Inducing Signaling Complex (DISC), caused by defective interaction with the CCZ1-MON1A complex, necessary to activate RAB7A and allow proper endosome/autophagosome maturation and fusion with lysosomes. We demonstrated that FYCO1 is a novel and specific caspase 8 substrate, and that the cleavage at aspartate 1306 inactivates its function, allowing for the progression of apoptosis. Furthermore, a lack of FYCO1 resulted in a more efficient and prolonged formation of the TNF-R signaling complex. Thus, FYCO1 limits the ligand-induced and steady-state signaling of TNFR-superfamily members, providing a natural control mechanism that fine tunes both apoptotic and inflammatory answers.