Figure 2: Regulation of necroptosis by the ripoptosome and necrosome.

Loss of checkpoint inhibition downstream of TNFR1 signaling leads to RIPK1 activation, causing complex I to shift to complex II. In the presence of limited caspase-8 activity, mediated by caspase-8/cFLIP_L heterodimers, complex IIa, or the ripoptosome, facilitates cell survival through RIPK1 cleavage. Full activation of caspase-8 by the formation of caspase-8 homodimers leads to RIPK1 cleavage and ripoptosome-mediated apoptosis. Loss or inhibition of caspase-8 activity leads to the formation of the necrosome, phosphorylation of RIPK3 and MLKL, and the induction of necroptosis.