ArticleProceedings of the National Academy of Sciences of the United States of America2025
A viral necrosome mediates direct RIPK3 activation to promote inflammatory necroptosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Interplay between SFTSV and host innate immunity: Viral evasion mechanisms, pathogenesis, and therapeutic perspectives.iScience · 2026Review
- Suppression of Calpain Attenuates Coxsackievirus B3-Induced Myocarditis by Regulating RIPK1/RIPK3/MLKL Pathway.Journal of cardiovascular translational research · 2026Article
- Time-Course Transcriptomic Analysis Reveals PANoptosis-CCL2 Axis in Herpes Simplex Keratitis.Investigative ophthalmology & visual science · 2026Article
- Rift Valley fever virus activates multiple cell death pathways in neurons.Journal of virology · 2026Article
- Recombinant Dabie bandavirus as a bivalent vaccine platform inducing protective immunity against intracellular pathogens and cancer.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Regulatory complexity and therapeutic targeting of the necroptosis network.Frontiers in immunology · 2026Review
- OTUD7B exacerbates atherosclerosis by promoting RIPK1-dependent vascular smooth muscle cell necroptosis.Frontiers in cardiovascular medicine · 2026Article
- Multidimensional mechanisms of SFTSV-host interactions: viral protein functions, mFrontiers in cellular and infection microbiology · 2026Review
- Research progress on antiviral drugs and vaccines for severe fever with thrombocytopenia syndrome.Frontiers in immunology · 2026Review
- ZBP1 as a dynamic monitor of viral replication: implications for therapeutic strategies.Frontiers in cellular and infection microbiology · 2026Review
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
Corrections and comments
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Necroptosis is an inflammatory programmed cell death pathway triggered by RIPK3 activation through one of the upstream RHIM-domain-containing proteins including RIPK1, TRIF, and ZBP1. Whether necroptosis can be activated independent of the upstream signaling pathways leading to inflammatory pathogenesis remains ambiguous. Here, we revealed a mechanism in which a viral protein mediates direct RIPK3 activation resulting in severe inflammatory pathogenesis in patients. The nonstructural protein NSs of a pathogenic hemorrhagic virus, SFTSV, interacts with the RIPK3 kinase domain and forms biocondensate to promote RIPK3 autophosphorylation and necroptosis activation in an RHIM-independent manner. In parallel, sequestration of RIPK3 within the NSs-RIPK3 condensate inhibited RIPK3-mediated apoptosis and promoted viral replication. Infection with an SFTSV NSs mutant virus not forming NSs condensate triggered pronounced apoptosis resulting in reduced viral replication and decreased fatality in vivo. Blocking SFTSV-triggered necroptosis through depletion of MLKL or treatment with a RIPK3-kinase inhibitor reduced viral inflammatory pathogenesis and fatality in vivo. In contrast, blocking SFTSV-triggered apoptosis through depletion of RIPK3 resulted in enhanced viral replication and increased fatality in vivo. The virus-triggered necroptosis correlated with severe inflammatory pathogenesis and lethality in virus-infected patients. The NSs-RIPK3 condensate may represent a necroptosis activation mechanism that promotes viral pathogenesis.
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