Cell death following formation of the RIPK1-dependent platform, also termed ripoptosome, complex-IIB, or necrosome. (A) cIAP1, cIAP2, and XIAP target RIPK1 and components of the ripoptosome (caspase-8 and cFLIP_L) for Ub-mediated inactivation. Following genotoxic stress, cytokine signaling-induced depletion of cIAPs, or SMAC-mimetic (SM) treatment, cIAP1, cIAP2, and XIAP levels rapidly decline and/or are inactivated. This allows formation and accumulation of the ripoptosome. In the presence of high levels of RIPK3 this can lead to necroptosis. cFLIP also regulates ripoptosome-mediated cell death. cFLIP_L prevents apoptosis and necroptosis, while FLIP_S inhibits apoptosis but promotes necroptosis. (B) Under steady-state conditions, the majority of RIPK1 appears to be “inaccessible,” preventing it from binding to partner proteins. Cytokine receptor stimulation can convert a small fraction of RIPK1 into an “accessible,” binding competent configuration. In the presence of cIAPs and XIAP, binding competent RIPK1 is targeted for Ub-mediated inactivation, most likely via proteasomal degradation. Under conditions where IAP levels are low, however, unmodified and binding-competent RIPK1 accumulates and can form the ripoptosome. In the presence of high levels of cFLIP_L, the ripoptosome is dissolved via caspase-8-cFLIP_L-mediated cleavage of RIPK1. When cFLIP_L levels are low, the ripoptosome can promote caspase-dependent or caspase-independent cell death.