Fig. 4

Schematic presentation of necroptosis pathway induced by tumor necrosis factor (TNF). The binding of TNF to its cognate receptor TNFR1 triggers the assembly of complex I, which includes TNFR1, TNFR1-associated death domain (TRADD), receptor-interacting serine/threonine protein kinase 1 (RIPK1), TNFR-associated factor 2 ( TRAF2), cellular inhibitor of apoptosis protein 1/2 (cIAP1/2), and linear ubiquitin chain assembly complex (LUBAC). Complex I provides a platform for a series of ubiquitination and deubiquitination reactions. This ubiquitination is related to nuclear factor-κB (NF-κB) or the decision between survival signals and cell death signals. Subsequently, the ubiquitination of RIPK1 by cIAP1 and cIAP2 stabilized complex I and made the further recruitment of additional factors. The cytoplasmic death-inducing signal complex composed of RIPK1/3, MLKL, caspase-8 and FAS- associated death domain protein (FADD) is called complex II. When RIPK3 and MLKL levels are sufficiently high and caspase-8 activity is inhibited, complex II may evolve to form necrosome. Upon receipt of a necroptosis-inducing stimulus, RIPK1 phosphorylates and activates RIPK3, which in turn phosphorylates and activates MLKL, forming a complex called necrosome. Then, MLKL is recruited and phosphorylated by RIPK3 to form active oligomers. The executor of necroptosis is MLKL, there are two non-exclusive models are proposed for the mechanism of MLKL. One could act directly as a direct pore-forming complex that is recruited through binding of the amino-terminus, another could act indirectly by serving as a platform that deregulates Ca²⁺ or Na⁺ ion channels