Fig. 4

Mechanisms of necroptosis. In TNFR signaling, complex I containing TRADD, RIPK1, TRAF2, E3 ubiquitin ligases, cIAP1/2, and LUBAC is unstable when RIP1K is deubiquitinated by CYLD, leading to the formation of the necrosome together with high levels of RIPK3 and MLKL as well as inhibited caspase-8. Subsequently, RIPK3 in the necrosome oligomerizes and is phosphorylated, leading to the recruitment and phosphorylation of MLKL, and phosphorylated MLKL translocates to the plasma membrane to cause membrane damage and necroptosis, or phosphorylated MLKL interacts with phosphorylase PGAM5 on the mitochondrial membrane and then activates mitochondrial fission factor Drp1 to induce necroptosis. In Fas/TRAILR signaling, when cIAPs are absent and caspase-8 is inhibited, the activation of Fas/TRAILR can induce necroptosis. In TLR3/4 signaling, their activation can induce TRIF-mediated necroptosis in the presence of zVAD-fmk, TLR4 activation by lipopolysaccharide (LPS) or TLR3 activation by polyinosine–polycytidylic acid. In DAI signaling, in response to viral double-stranded DNA, DAI also mediates RIPK3-dependent necroptosis under certain conditions