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

ABSTRACT: TNF 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Sudan He

PROVIDER: PXD073919 | iProX | Mon Feb 02 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:This model is from the article: Heterogeneity Reduces Sensitivity of Cell Death for TNF-Stimuli Schliemann M, Bullinger E, Borchers S, Allgower F, Findeisen R, Scheurich P. BMC Syst Biol. 2011 Dec 28;5(1):204. 22204418 , Abstract: BACKGROUND: Apoptosis is a form of programmed cell death essential for the maintenance of homeostasis and the removal of potentially damaged cells in multicellular organisms. By binding its cognate membrane receptor, TNF receptor type 1 (TNF-R1), the proinflammatory cytokine Tumor Necrosis Factor (TNF) activates pro-apoptotic signaling via caspase activation, but at the same time also stimulates nuclear factor kappaB (NF-kappaB)-mediated survival pathways. Differential dose-response relationships of these two major TNF signaling pathways have been described experimentally and using mathematical modeling. However, the quantitative analysis of the complex interplay between pro- and anti-apoptotic signaling pathways is an open question as it is challenging for several reasons: the overall signaling network is complex, various time scales are present, and cells respond quantitatively and qualitatively in a heterogeneous manner. RESULTS: This study analyzes the complex interplay of the crosstalk of TNF-R1 induced pro- and anti-apoptotic signaling pathways based on an experimentally validated mathematical model. The mathematical model describes the temporal responses on both the single cell level as well as the level of a heterogeneous cell population, as observed in the respective quantitative experiments using TNF-R1 stimuli of different strengths and durations. Global sensitivity of the heterogeneous population was quantified by measuring the average gradient of time of death versus each population parameter. This global sensitivity analysis uncovers the concentrations of Caspase-8 and Caspase-3, and their respective inhibitors BAR and XIAP, as key elements for deciding the cell's fate. A simulated knockout of the NF-kappaB-mediated anti-apoptotic signaling reveals the importance of this pathway for delaying the time of death, reducing the death rate in the case of pulse stimulation and significantly increasing cell-to-cell variability. CONCLUSIONS: Cell ensemble modeling of a heterogeneous cell population including a global sensitivity analysis presented here allowed us to illuminate the role of the different elements and parameters on apoptotic signaling. The receptors serve to transmit the external stimulus; procaspases and their inhibitors control the switching from life to death, while NF-kappaB enhances the heterogeneity of the cell population. The global sensitivity analysis of the cell population model further revealed an unexpected impact of heterogeneity, i.e. the reduction of parametric sensitivity. Note: SBML model generated from Matlab system description on 12-July-2011 21:08:15 by exportSBML Copyright Eric Bullinger 2007-2011

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

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