ArticleThe EMBO journal2024
A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses.
Article in The EMBO journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Biological consequences of Z-nucleic acid sensing by ZBP1 and ADAR1.RNA biology · 2026Review
- Mechanisms, regulation and clinical relevance of necroptosis.Nature reviews. Molecular cell biology · 2026Review
- The Role of cGAS-STING-Driven PANoptosis in Neurodegenerative Diseases and Therapeutic Prospects.Cells · 2026Review
- Z-nucleic acid-mediated PANoptosis in infection, inflammation, and cancer.Communications biology · 2026Review
- Defining critical roles for ZBP1 in PANoptosis utilizing a novel genetic tool for disease modeling and therapeutic development.bioRxiv : the preprint server for biology · 2026Article
- Zα and Zβ domains of ADAR1 and ZBP1 bind G-quadruplexes with nanomolar affinities, establishing Zβ as a G-quadruplex-specific domain.Nucleic acids research · 2026Article
- Formation and biological implications of Z-DNA.Trends in genetics : TIG · 2026Review
- ZBP1 as a dynamic monitor of viral replication: implications for therapeutic strategies.Frontiers in cellular and infection microbiology · 2026Review
- Research progress in PANoptosis mechanisms and their interplay with tuberculosis.Frontiers in cellular and infection microbiology · 2026Review
- Regulatory complexity and therapeutic targeting of the necroptosis network.Frontiers in immunology · 2026Review
- Zbp1 promotes atherosclerosis and lesion necrosis in mice.Atherosclerosis · 2025Article
- Necroptotic cell death consequences and disease relevance.Nature immunology · 2025Review
- Necroptosis in cancer: insight from epigenetic, post-transcriptional and post-translational modifications.Journal of hematology & oncology · 2025Review
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Authors and funding
4 authors.
Funding
Abstract
Z-DNA-binding protein 1 (ZBP1) is an interferon-inducible sensor of Z-DNA and Z-RNA, which has emerged as a critical regulator of cell death and inflammation. ZBP1 binds Z-DNA and Z-RNA via its Zα domains, and signals by engaging RIPK3 and RIPK1 via its RIP homotypic interaction motifs (RHIMs). Here, we show that mice express an alternatively-spliced shorter ZBP1 isoform (ZBP1-S), which harbours the Zα domains but lacks the RHIMs, and acts as an endogenous inhibitor of the full-length protein (ZBP1-L). Mice and cells expressing only ZBP1-S are resistant to ZBP1-mediated cell death and inflammation. In contrast, cells lacking ZBP1-S show increased ZBP1-L-induced death compared to cells expressing both isoforms. Moreover, loss of the short isoform accelerates and exacerbates skin inflammation induced by ZBP1-mediated necroptosis of RIPK1-deficient keratinocytes, revealing an important physiological role of ZBP1-S. Mechanistically, ZBP1-S suppresses ZBP1-L-mediated cell death by binding to Z-nucleic acids via its Zα domains. Therefore, ZBP1-S acts as an endogenous inhibitor that competes with full-length ZBP1-L for binding Z-nucleic acid ligands to fine-tune ZBP1-mediated cell death and inflammation.
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