Figure 2.

Pleiotropic TNF signaling pathways. (1) Inflammation and cell survival. Engagement of TNF with its receptor TNFR1 leads to the recruitment of RIPK1 and TRADD through death domain interactions to initiate complex I formation. TRADD then recruits adaptor protein TRAF2/5, which binds E3 ligase cIAP1/2. cIAP1/2 catalyzes K63 ubiquitination of RIPK1, serving as a scaffold to recruit ubiquitin-binding proteins TAB2/3 and associated TAK1, activating the downstream MAPK pathway. Additionally, the K63 ubiquitin chain recruits another E3 complex, LUBAC, which catalyzes the M1 linear ubiquitin chains on RIPK1 and TNFR1. These linear ubiquitin chains recruit adaptor protein NEMO and associated IKKα/β, phosphorylating IκBα to promote its degradation and subsequent NF-κB activation. Both the MAPK pathway and the NF-κB pathway activate gene expression, which promotes cell survival and inflammation. (2) Apoptosis and/or pyroptosis. Under TNF treatment with protein synthesis inhibition by cycloheximide (CHX), complex I is converted to complex IIa, containing TRADD, FADD, and Caspase-8, leading to oligomerization and activation of Caspase-8 and subsequent apoptosis. Alternatively, co-treatment of TNF with a cIAP1/2 inhibitor, Smac-mimetic, converts complex I to complex IIb, containing RIPK1, FADD, and Caspase-8, which also activates Caspase-8 and apoptosis. Under some circumstances, such as during Yersinia infection, activated Caspase-8 cleaves gasdemin D or E to trigger pyroptosis. (3) Necroptosis. Inhibition of apoptosis with Z-VAD-FMK, along with the presence of RIPK3, leads to the conversion of complex II into the necrosome. The core components of the necrosome include RIPK1, RIPK3, and MLKL, resulting in polymerization and membrane translocation of MLKL and subsequent cell death. In general, the scaffold function of RIPK1 is important for inflammation and cell survival, while the kinase activity is important for complex IIb-dependent apoptosis as well as necroptosis. Under some circumstances, such as during pathogen infection, simultaneous activation of pyroptosis, apoptosis, and necroptosis occurs, which is defined as PANoptosis. Abbreviations: TNF, tumor necrosis factor; TRAF2/5, TNF receptor-associated factor protein 2/5; cIAP1/2, cellular inhibitor of apoptosis 1 and 2; TAB2/3, TAK1-binding protein 2/3; TAK1, transforming growth factor-β-activated kinase 1; LUBAC, the linear ubiquitin chain assembly complex; NEMO, NF-κB essential modulator; IKKα/β, IκB kinase α/β; IκBα, inhibitor of kB alpha; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase; MLKL, mixed-lineage kinase-like protein; CHX, cycloheximide; Smac-mimetic, Second Mitochondria-derived Activator of Caspases-mimetic. The red stripes in the diagram of RIPK1 and RIPK3 indicate the RHIM domain.