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. 2023 Jul 1;16:2727–2754. doi: 10.2147/JIR.S417801

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© 2023 Liu et al.

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Signaling pathway of Necroptosis. The binding of TNF-α to tumor necrosis factor receptor 1 (TNFR1) promotes the assembly of complex I, including TNFR1, TNFR1-associated death domain (TRADD), receptor-interacting serine/threonine protein kinase 1 (RIPK1), TNFR-linked factor 2 (TRAF2), apoptosis protein (cIAP), and deubiquitinating enzymes such as CYLD. Complex I offers a platform for a series of subsequent ubiquitination and de-ubiquitination reactions, in which cIAP keeps RIPK1 ubiquitinated, while CYLD makes RIPK1 de-ubiquitinated. When caspase-8 is blocked, the ubiquitination of RIPK1 causes the formation of complex IIb. In complex IIb, RIPK1 is autophosphorylated, which subsequently recruits and stimulates RIPK3. PIPK3 further recruits and phosphorylates MLKL to create necrosomes. RIPK3 can also be independently stimulated by TIR-domain-containing adapter-inducing interferon-β (TRIF), an adapter protein of Toll-like receptors (TLRs). Eventually, phosphorylated MLKL oligomerizes and translocates to the cell membrane to develop plasma membrane pores, inducing plasma membrane rupture and cell disintegration.