ArticleProceedings of the National Academy of Sciences of the United States of America2014
Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 158 papers.
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158 citing papers in PubMed, 226 citations in OpenAlex.
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- PANoptosis as a Therapeutic Target for COVID-19.Current microbiology · 2026Review
- Z-DNA binding protein 1 mediates necroptotic cell death in primary murine microglia following herpes simplex virus-1 infection.Journal of neurovirology · 2026Article
- The evolutionary arms race on the Z-form-nucleic- acid-binding protein 1 front: endogenous Z-RNA as a self-danger signal.Molecular biomedicine · 2026Article
- vIRA Inhibition of Antiviral Necroptosis and RIPK3 Binding Are Separable Events.Pathogens (Basel, Switzerland) · 2026Article
- Monogenic disorders of the TNF signalling pathway.Nature reviews. Rheumatology · 2026Review
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- Mammalian innate antiviral defenses: beyond interferon.Journal of virology · 2025Review
- Recombinant Oncolytic Viruses: Hexagonal Warriors in the Field of Solid Tumor Immunotherapy.Current issues in molecular biology · 2025Review
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- Tea Polyphenols Mitigate TBBPA-Induced Renal Injury Through Modulation of ROS-PI3K/AKT-NF-κB Signalling in Carp (Animals : an open access journal from MDPI · 2025Article
- UVB-Induced necroptosis of the skin cells via RIPK3-MLKL activation independent of RIPK1 kinase activity.Cell death discovery · 2025Article
- Differential homing of monocytes and neutrophils in the epithelial layer of HSV-1 infected cornea regulates viral dissemination and wound healing.The ocular surface · 2025Article
- The Interplay Between Viral Infection and Cell Death: A Ping-Pong Effect.Advances in virology · 2025Review
- Bat RNA viruses employ viral RHIMs orchestrating species-specific cell death programs linked to Z-RNA sensing and ZBP1-RIPK3 signaling.iScience · 2024Article
- Review
98 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 4 institutions in 2 countries.
Funding
Abstract
The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.