Figure 3.

Necroptotic signaling pathway exemplified by tumor necrosis factor alpha (TNF-α)-mediated activation of tumor necrosis factor receptor (TNFR)1. Activated TNFR1 forms a multi-protein complex I that transmit either pro-survival response (NF-κB activation) or cell death response, which is mediated by cylindromatosis (CYLD)-dependent deubiquitylation of receptor-interacting protein kinase 1 (RIPK1). Complexes-IIa/b are formed when the activation of caspase-8 can proceed apoptosis. Upon inhibition of caspase-8, complex IIc (necrosome) mediates activation of mixed lineage kinase domain-like (MLKL) by phosphorylation at Ser³⁵⁸ that results in pore formation in the plasma membrane and Ca²⁺ influx. Compounds that inhibit necroptosis, including necrostatin-1 (Nec-1), necrostatin-1s (Nec-1s), and necrosulfonamide (NSA) are shown in orange background.