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. 2022 Oct 4;30(2):237–249. doi: 10.1038/s41418-022-01059-z

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — TRAIL-mediated death receptor trimerization enables the recruitment of FADD, which in turn binds to procaspase-8 to form the DISC. TRAIL-Rs, FADD and caspase-8 appear to exist in a 3:1:9 (Receptor:FADD:Caspase) stoichiometry [143]. cFLIP isoforms differentially control TRAIL signaling. Caspase-8 oligomerization and activation can be facilitated by the E3-ligases Cullin-3 which mediates K48/K63 ubiquitination of caspase-8 and subsequent recruitment of the Ub-binding protein p62 to the DISC, allowing p62-mediated aggregation and full activation of the caspase-8caspase-8 [144]. Following ubiquitination of caspase-8, TNFR-associated factor 2 (TRAF2) interacts with caspase-8 at the DISC, down-stream of Cullin3 and it is required for K48-linked polyubiquitination on the large catalytic domain of caspase-8, hence, triggering the proteasomal degradation of this protease and serving as a shut-off timer for the death ligand-mediated apoptosis [145]. In type I cells, DISC-activated caspase-8 is sufficient to activate caspease-3 and trigger apoptosis by the extrinsic pathway. In type II cells full activation of caspase-3 is inhibited by XIAP and therefore activation of the intrinsic apoptosis pathway is essential for full activation of caspease-3. Caspase-8 mediated activation of tBid triggers Bax and Bak to execute mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of second mitochondria-derived activator of caspase (SMAC), thereby enabling the full activation of caspase-3. Additionally, cytochrome c is also released from the mitochondria and along with adaptor protein apoptosis protease-activating factor-1 (Apaf-1) forms the apoptosome which activates caspase-9, to enable amplification of caspase-3 activation and apoptosis. Upon TRAIL stimulation, following DISC assembly, a secondary cytoplasmatic complex can be formed, known as complex II, which retains the DISC components FADD, caspase-8 and RIPK1. In absence of caspase-8 or when its activity is blocked, RIPK1 recruits RIPK3, which in turn phosphorylates MLKL. Phosphorylated MLKL then oligomerises, which results in the execution of necroptosis.