Cell Death-Associated Molecular-Pattern Molecules: Inflammatory Signaling and Control
Figure 4
Schematic overview of TNF-α-induced signaling pathways to activation of NF-κB (a), apoptosis (b), and necroptosis (c). TNF-α binding to TNFR causes the assembly of a membrane-proximal supramolecular complex including (but not limited to) TRADD, FADD, TRAF2/5 (TNFR associated factor 2/5), cIAP1/2 (cellular inhibitor of apoptosis 1/2), and RIPK1 (receptor interacting protein kinase). RIPK1 causes the phosphorylation and activation of TAK1/TAB2/3 which in turn promote the phosphorylation of the inhibitor of NF-κB (IKK subunits α, β, and γ). The ubiquitination leads to the proteasome-mediated degradation of IκBα and release and nuclear translocation of NF-κB dimers. Recruitment and activation of caspase-8 play a crucial role in initiation of apoptotic (b) or necrotic cell death (c). Cleavage of both RIP1 and RIP3 by caspase-8 leads to apoptosis, whereas phosphorylation of RIP1 and RIP3 kinases causes the necrosome activation. Similarly, caspase-8 inhibition, or FADD/caspase-8 deletion, or RIPK3 induction leads to necrosome activation. Both RIPK1 and RIPK3 phosphorylate and activate a mixed lineage kinase domain-like (MLKL) and phosphoglycerate mutase family member 5 (PGAM5L and S) which recruit dynamin-related protein 1 (Drp-1), one of the key regulators of mitochondrial fission and mitochondrial fragmentation-dependent signaling pathway leading to necroptosis.
