Fig. 2.

Necroptosis pathway. TNF receptors induce formation of complex I. If receptor-interacting protein kinase (RIP)1 remains ubiquitinated, the cell survives. Complex I forms complex II by deubiquitination of RIP1, and it is mediated by loss of cellular inhibitor of apoptosis 1/2 (cIAP1/2). Caspase 8 activation in complex II inhibits RIP3 and promotes apoptosis, whereas caspase inactivation promotes necroptosis by phosphorylating RIP1, which in turn phosphorylates RIP3. Phosphorylated RIP3 causes mixed-lineage kinase domain-like (MLKL) phosphorylation that triggers MLKL oligomerization and subsequently translocation to the cell membrane, where it makes pore and release damage-associated molecular patterns (DAMPs).