GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE318nnn/GSE318316/primaryOK200OtherHomo sapiensOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE318316GEOGSEfalseHERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell deathTNF can activate both pro-survival and pro-death signaling downstream of tumor necrosis factor receptor 1 (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 the molecular determinant of pro-survival or pro-death signaling. We show that 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. We show that HERC4 is the link enabling Complex I-derived kinase-active RIPK1 to initiate death signaling.2026/07/14GSE318316GSM9492287GSM949228824676318316Homo sapiens