Death-receptor activation halts clathrin-dependent endocytosis

Abstract

Endocytosis is crucial for various aspects of cell homeostasis. Here,we show that proapoptotic death receptors (DRs) trigger selectivedestruction of the clathrin-dependent endocytosis machinery. DRstimulation induced rapid, caspase-mediated cleavage of keyclathrin-pathway components, halting cellular uptake of the classiccargo protein transferrin. DR-proximal initiator caspases cleavedthe clathrin adaptor subunit AP2 between functionally distinctdomains, whereas effector caspases processed clathrin’s heavychain. DR5 underwent ligand-induced, clathrin-mediated endocytosis,suggesting that internalization of DR signaling complexesfacilitates clathrin-pathway targeting by caspases. An endocytosisblocking,temperature-sensitive dynamin-1 mutant attenuated DRinternalization, enhanced caspase stimulation downstream of DRs,and increased apoptosis. Thus, DR-triggered caspase activity disruptsclathrin-dependent endocytosis, leading to amplification ofprogrammed cell death.