Fig. 3

TNFR1-elicited signaling pathways [133]. a On tumor necrosis factor (TNF) binding, TNF receptor 1 (TNFR1) undergoes a conformational change, allowing for the intracellular assembly of the so-called TNFR complex I, which includes TNF receptor-associated death domain (TRADD), receptor-interacting protein 1 (RIP1; also known as RIPK1), cellular inhibitor of apoptosis proteins (cIAPs), TNF receptor-associated factor 2 (TRAF2) and TRAF5. On cIAP-mediated Lys63-ubiquitylation, RIP1 can serve as a scaffold for the recruitment of transforming growth factor-β activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) and TAB3, which initiate the canonical nuclear factor-κB (NF-κB) activation pathway. Riboflavin kinase (RFK) physically bridges the TNFR1 death domain to p22phox (also known as CYBA), the common subunit of multiple NADPH oxidases, including NADPH oxidase 1 (NOX1), which also contributes to TNFα-induced necroptosis by generating reactive oxygen species (ROS). Conversely, on deubiquitylation by cylindromatosis (CYLD; and perhaps also by A20 (also known as TNFAIP3), cezanne (also known as OTUD7B) or ubiquitin-specific peptidase 21 (USP21)), RIP1 exerts lethal functions, which can be executed by two distinct types of cell death. b The internalization of TNFR1 is accompanied by a change in its binding partners that leads to the cytosolic assembly of TNFR complex II, which often (but not invariably) contains TRADD, FAS-associated protein with a death domain (FADD), caspase-8, RIP1, and RIP3 (also known as RIPK3). Normally, caspase-8 triggers apoptosis by activating the classical caspase cascade. It also cleaves, and hence inactivates, RIP1 and RIP3. c If caspase-8 is blocked by pharmacological or genetic interventions, RIP1 and RIP3 become phosphorylated (perhaps by an unidentified kinase) and engage the effector mechanisms of necroptosis. FAD flavin adenine nucleotide, FMN flavin mononucleotide