Publikation: Proteasome inhibition triggers the formation of TRAIL receptor 2 platforms for caspase-8 activation that accumulate in the cytosol
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Cancer cells that are resistant to Bax/Bak-dependent intrinsic apoptosis can be eliminated by proteasome inhibition. Here, we show that proteasome inhibition induces the formation of high molecular weight platforms in the cytosol that serve to activate caspase-8. The activation complexes contain Fas-associated death domain (FADD) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Furthermore, the complexes contain TRAIL-receptor 2 (TRAIL-R2) but not TRAIL-receptor 1 (TRAIL-R1). While RIPK1 inhibition or depletion did not affect proteasome inhibitor-induced cell death, TRAIL-R2 was found essential for efficient caspase-8 activation, since the loss of TRAIL-R2 expression abrogated caspase processing, significantly reduced cell death, and promoted cell re-growth after drug washout. Overall, our study provides novel insight into the mechanisms by which proteasome inhibition eliminates otherwise apoptosis-resistant cells, and highlights the crucial role of a ligand-independent but TRAIL-R2-dependent activation mechanism for caspase-8 in this scenario.
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HELLWIG, Christian T., M. Eugenia DELGADO, Josip SKOKO, Lydia DYCK, Carol HANNA, Alexa WENTGES, Claudia LANGLAIS, Cathrin HAGENLOCHER, Alexandra MACK, Markus REHM, 2022. Proteasome inhibition triggers the formation of TRAIL receptor 2 platforms for caspase-8 activation that accumulate in the cytosol. In: Cell Death and Differentiation. Nature Publishing Group. 2022, 29(1), pp. 147-155. ISSN 1350-9047. eISSN 1476-5403. Available under: doi: 10.1038/s41418-021-00843-7BibTex
@article{Hellwig2022-01Prote-54739, year={2022}, doi={10.1038/s41418-021-00843-7}, title={Proteasome inhibition triggers the formation of TRAIL receptor 2 platforms for caspase-8 activation that accumulate in the cytosol}, number={1}, volume={29}, issn={1350-9047}, journal={Cell Death and Differentiation}, pages={147--155}, author={Hellwig, Christian T. and Delgado, M. Eugenia and Skoko, Josip and Dyck, Lydia and Hanna, Carol and Wentges, Alexa and Langlais, Claudia and Hagenlocher, Cathrin and Mack, Alexandra and Rehm, Markus} }
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