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|Title:||Receptor-mediated endocytosis is not required for TRAIL-induced apoptosis|
|Other Titles:||Receptor-mediated endocytosis is not required for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis|
|Authors:||Kohlhaas, Susan Louise|
Pinkoski, Michael J.
Cohen, Gerald M.
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Citation:||Journal of Biological Chemistry, 2007, 282(17), pp.12831-12841|
|Abstract:||Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is selectively toxic to tumor compared to normal cells. Other members of the TNF family of death ligands (Tumor necrosis factor, CD95L) engage their respective receptors (TNF-R1 and CD95), resulting in internalization of receptor and ligand and recruitment of adaptor proteins to the caspase activation platform known as the death-inducing signalling complex (DISC). Recently, TNF-R1 and CD95 have been shown to induce apoptosis with an absolute requirement for internalization of their corresponding receptors in the formation of a DISC. We show that TRAIL and its receptors are rapidly endocytosed in a time- and concentration-dependent manner. Blockade of receptor internalization with hyperosmotic sucrose did not inhibit TRAIL-induced apoptosis but rather amplified the apoptotic signalling of TRAIL. Plate-bound and soluble TRAIL induced similar levels of apoptosis. Together these results suggest that neither ligand nor receptor internalization are required for TRAIL-induced apoptosis. Internalization of TRAIL is mediated primarily by clathrin- dependent endocytosis and also by clathrin-independent pathways. Inhibition of clathrin-dependent internalization by overexpression of dominant negative forms of dynamin or AP180 did not inhibit TRAIL-induced apoptosis. Consistent with the finding that neither internalization of TRAIL nor its receptors are required for transmission of its apoptotic signal, recruitment of FADD and procaspase-8 to form the TRAIL-associated DISC occurred at 4 oC, independent of endocytosis. Our findings demonstrate that TRAIL and TRAIL-R1/R2, unlike TNFTNF-R1 or CD95L-CD95, do not require internalization for formation of the DISC, activation of caspase-8 or transmission of an apoptotic signal in BJAB type I cells.|
|Rights:||This is the authors' final draft of the paper published as Journal of Biological Chemistry, 2007, 282(17), pp.12831-12841. The definitive version is available from http://www.jbc.org/, doi:10.1074/jbc.M700438200.|
|Appears in Collections:||Published Articles, MRC Toxicology Unit|
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