Article Impact Level: HIGH Data Quality: STRONG Summary of Nature Structural & Molecular Biology https://doi.org/10.1038/s41594-026-01871-y Dr. Haohao Lu et al.
Points
- International researchers identified the E3 ubiquitin ligase HERC4 as the essential molecular switch driving tumor necrosis factor induced apoptosis and necroptosis cell death pathways.
- Mechanistic experiments revealed that HERC4 selectively binds S166 phosphorylated kinase active RIPK1 in Complex I and ubiquitinates its death domain to form cytosolic Complex II.
- In vivo studies demonstrated that knockout mice lacking HERC4 were protected from severe systemic inflammatory response syndrome and acute liver damage triggered by uncontrolled cell death.
- Pharmacological targeting of HERC4 offers a potential oral therapeutic strategy for chronic inflammatory conditions including rheumatoid arthritis inflammatory bowel disease and psoriasis.
- Authors concluded that HERC4 mediated ubiquitination resolves a key mechanism in receptor signaling and provides a promising target for next generation anti inflammatory drug development.
Summary
This study evaluated the molecular mechanisms governing tumor necrosis factor (TNF)-induced cell death pathways downstream of tumor necrosis factor receptor 1 (TNFR1). Published in Nature Structural and Molecular Biology by international researchers from the Chinese Academy of Medical Sciences, the University of Cologne, UCL Cancer Institute, and the National Institute of Biological Sciences, the investigation solved a long-standing question in immune signaling. The research sought to identify the specific molecular switch converting receptor-interacting protein kinase 1 (RIPK1) from a prosurvival scaffold in membrane-bound Complex I into a prodeath kinase in cytosolic Complex II.
Using a knockout screen designed to identify proteins regulating RIPK1 ubiquitination, researchers identified the E3 ubiquitin ligase HERC4 as the essential component required for TNF-induced apoptosis and necroptosis. Mechanistic analyses revealed that HERC4 specifically binds to Complex I-derived, S166-phosphorylated, kinase-active RIPK1 and ubiquitinates it within its death domain. This post-translational modification enables RIPK1 oligomerization and drives the assembly of apoptosis-inducing Complex IIa (comprising RIPK1, RIPK3, FADD, caspase-8, and cFLIP) or, upon caspase inhibition, the necroptosis-initiating necrosome. In vivo validation demonstrated that HERC4 deficiency fully protected mouse models against TNF-induced systemic inflammatory response syndrome (SIRS) and acute liver injury.
The authors conclude that HERC4 is the critical molecular determinant enabling Complex I-derived RIPK1 to initiate cell death signaling. By regulating the transition from survival signaling to programmed cell death, HERC4 represents a novel therapeutic target for chronic inflammatory conditions, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Developing small-molecule HERC4 inhibitors may provide an oral alternative to injectable TNF inhibitors with potentially broader clinical efficacy across inflammatory and autoimmune diseases.
Link to the article: https://www.nature.com/articles/s41594-026-01871-y
References
Lu, H., Du, T., Li, L., Cao, D., Li, K., Liu, L., Li, R., Yu, X., Hou, S., Wang, X., Shi, M., Liu, Y., Ma, F., Chen, S., Walczak, H., & He, S. (2026). HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death. Nature Structural & Molecular Biology, 1–14. https://doi.org/10.1038/s41594-026-01871-y
