Figure 3.

Schematic illustration of the major TNFR1-mediated signaling pathways. After binding of TNF to TNFR1 the signaling complex I is formed in the plasma membrane consisting of TRADD, RIP1, TRAF2, and cIAP1/2 and the protein complexes TAB2/TAB3/TAK1 and LUBAC. This complex I mediates the activation of the NFκB pathway via activation of the IKK complex resulting in phosphorylation and degradation of IκB and translocation of NFκB to the nucleus. NFκB binding to the DNA can then, for example, induce expression of proinflammatory cytokines, cell adhesion molecules, and ROS generating enzymes. Moreover, complex I can induce, via distinct MAP kinase kinases (MKK), the activation of the stress-activated kinases p38 MAPK and JNK, which can both induce gene transcription (not shown). In the cytosol, sustained activation of p38 and JNK can induce cell death via apoptosis. After TNFR1 internalization, a distinct signaling complex II is formed consisting of TRADD, FADD, and the procaspase 8. After autoproteolytic activation caspase 8 can cleave RIP1 and RIP3, which is followed by the induction of apoptosis either directly or by targeting the mitochondrion. If caspase 8 activity is insufficient, RIP1 and RIP3 can induce the alternative cell death program of necroptosis via their kinase activities. Here, a central step is the phosphorylation of MLKL by RIP3.