iProXProteomicsSudan HeHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0015540000hesudan2018@163.comSuzhou Institute of Systems MedicineiProXfalseHERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell deathTNF can activate both pro-survival and pro-death signaling downstream of TNFR1. Survival signaling originates from TNFR1-containing membrane-bound Complex I, while death signaling is driven by cytosolic Complex II. RIPK1 is a central component of both complexes, but the molecular switch converting RIPK1 from a pro-survival scaffold in Complex I to a pro-death kinase in Complex II has remained elusive. Here, we identify the E3 ligase HERC4 as this crucial switch. HERC4 binds Complex-I-derived S166-phosphorylated, kinase-active RIPK1 and ubiquitinates it within its death domain. This enables RIPK1 oligomerization and assembly of the apoptosis-inducing RIPK1–FADD–caspase-8-containing Complex IIa and, upon caspase inhibition, formation of the necroptosis-initiating RIPK1–RIPK3-containing necrosome. HERC4 deficiency protects mice from TNF-induced systemic inflammatory response syndrome and acute liver injury. HERC4 is thus the missing link enabling Complex I-derived kinase-active RIPK1 to initiate death signaling and represents a previously unrecognized therapeutic entry point for cell-death-dependent TNF-induced inflammatory diseases.Mon Feb 02 00:00:00 GMT 2026PXD0739199606