TRADD:TRAF2:RIP1:FADD complex binds Pro-Caspase 8

Stable Identifier
R-HSA-75240
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Human cytomegalovirus
Compartment
ReviewStatus
5/5
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Tumor necrosis factor α (TNF-α)-induced apoptosis is regulated by the activity of caspase-8 (CASP8) (Micheau O and Tschopp J 2003; Justus SJ and Ting AT 2015). CASP8 is synthesized as an inactive precursor, pro-caspase-8, which is recruited to the cytosolic TRADD:TRAF2:RIPK1:FADD complex upon stimulation. Within this complex, multiple procaspase‑8 molecules interact via their tandem death‑effector domains (DED), thereby facilitating both proximity‑induced dimerization and proteolytic cleavage of procaspase‑8, which are required for initiation of apoptotic cell death (Keller N et al 2009; Oberst A et al. 2010). Activated CASP8 mediates cleavage and activation of effector caspases such as CASP3 to promote apoptosis, while cleavage of RIPK1, RIPK3 by CASP8 prevents RIPK1:RIPK3-dependent necroptosis (Parrish AB et al. 2013; Hopkins-Donaldson S et al. 2000; Newton K et al. 2019; Lalaoui N et al. 2020). When apoptosis is blocked, which occurs naturally in some cells or under certain pathophysiological conditions (e.g., expression of CASP8 inhibitory proteins such as CrmA and vICA after infection with cowpox virus or CMV and/or protein synthesis blockade that prevents NF-kappa-B-mediated expression of FLICE-inhibitory protein (cellular FLIP, CFLAR), deubiquitinated RIPK1 interacts with RIPK3 and MLKL to trigger necroptosis (Ofengeim D et al. 2015; Yuan J et al. 2019).

This Reactome event shows pro-CASP8 binding to the cytosolic TRADD:TRAF2:RIPK1:FADD complex. This binding event is negatively regulated by optineurin (OPTN) (Nakazawa S et al. 2016).

Literature References
PubMed ID Title Journal Year
12887920 Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes

Micheau, O, Tschopp, J

Cell 2003
Participants
Participates
This event is regulated
Negatively by