Abstract
Death effector domains (DEDs) are protein–protein interaction domains initially identified in proteins such as FADD, FLIP and caspase-8 involved in regulating apoptosis. Subsequently, these proteins have been shown to have important roles in regulating other forms of cell death, including necroptosis, and in regulating other important cellular processes, including autophagy and inflammation. Moreover, these proteins also have prominent roles in innate and adaptive immunity and during embryonic development. In this article, we review the various roles of DED-containing proteins and discuss recent developments in our understanding of DED complex formation and regulation. We also briefly discuss opportunities to therapeutically target DED complex formation in diseases such as cancer.
Highlights
Death effector domains (DEDs)-containing proteins form a variety of complexes that regulate key cellular processes, most notably apoptosis, necroptosis and autophagy
This stoichiometry is in agreement with data by Esposito et al.,[43] who reported a ratio of 5 × CD95:5 × FADD together with some 6 × CD95:5 × FADD and 7 × CD95:5 × FADD ratios, but not the 4 × CD95:4 × FADD suggested by Scott et al Disparities between these models could be explained by the different conditions used for protein crystallisation; the models proposed by Wang et al and Esposito et al are supported by the fact that they account for mutations frequently seen in autoimmune lymphoproliferative syndrome
RIPK1 is conjugated by K63 ubiquitin chains inducing two distinct signaling pathways from the TRADDosome: firstly, NF-κB signaling through NEMO, IKKα and IKKβ, and secondly NEMO can interact with NAP1, TBK1 and IKKε to activate IRF3 or IRF7.205–208 In addition to caspase-8, the TRADDosome can recruit FLIP and may under certain conditions, trigger cell death
Summary
Does caspase-10 (absent in mice) have overlapping functions with caspase-8, or is it functionally distinct?. What are the best ways of targeting DED-containing proteins to therapeutically activate cell death (e.g., in cancers) or prevent cell death (e.g., in neurodegenerative diseases)?. Are DED-containing proteins potential therapeutic targets for inflammatory diseases?. A number of actively regulated non-apoptotic mechanisms of cell death have emerged, including necroptosis, pyroptosis and ferroptosis, which have been comprehensively reviewed elsewhere.[2,3] Here, we focus on those mechanisms of cell death arising following stimulation of death receptors, broadly termed the ‘extrinsic pathway’. The DED-containing proteins, which are key decision makers in determining the life and death of cells, are the primary focus of this review. We will first introduce the main members of the DED protein family and discuss advances in the understanding of the assembly and stoichiometry of death receptor complexes. We will summarise the recent literature surrounding the regulation of these complexes and consider the role of these proteins in disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
