HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death.

HERC4 ubiquitinates S166-phosphorylated, kinase-active RIPK1 within its death domain, enabling RIPK1 oligomerization and formation of TNF-driven complex IIa and necrosome.

• Why it matters: TNF signaling can promote survival or death through TNFR1, but the molecular switch that converts RIPK1 from complex I scaffold to complex II death kinase was unclear.
• What they did: The study identified HERC4 as an E3 ligase that binds complex I-derived S166-phosphorylated RIPK1 and ubiquitinates it in the death domain, promoting complex IIa assembly and necrosome formation under caspase inhibition.
• The result: In mice, HERC4 deficiency protects against TNF-induced systemic inflammatory response syndrome and acute liver injury, linking complex I-derived RIPK1 to death signaling.

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