Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis
Open accessAbstract
Nucleic acids are potent triggers for innate immunity. Double‐stranded DNA and RNA adopt different helical conformations, including the unusual Z‐conformation. Z‐DNA/RNA is recognised by Z‐binding domains (ZBDs), which are present in proteins implicated in antiviral immunity. These include ZBP1 (also known as DAI or DLM‐1), which induces necroptosis, an inflammatory form of cell death. Using reconstitution and knock‐in models, we report that mutation of key amino acids involved in Z‐DNA/RNA binding in ZBP1's ZBDs prevented necroptosis upon infection with mouse cytomegalovirus. Induction of cell death was cell autonomous and required RNA synthesis but not viral DNA replication. Accordingly, ZBP1 directly bound to RNA via its ZBDs. Intact ZBP1‐ZBDs were also required for necroptosis triggered by ectopic expression of ZBP1 and caspase blockade, and ZBP1 cross‐linked to endogenous RNA. These observations show that Z‐RNA may constitute a molecular pattern that induces inflammatory cell death upon sensing by ZBP1.
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RIPK3 can be activated following RHIM-dependent interaction with ZBP1, which operates as sensor for cytosolic DNA-promoting type I IFN synthesis and NF-κB activation.
“or (2) ZBP1, which operates as a sensor for cytosolic DNA-promoting type I interferon (IFN) synthesis and NF-κB activation [439–441].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [439]
RIPK3 can be activated by proteins involved in innate immunity including TRIF and ZBP1.
“As mentioned above, RIPK3 can be activated by proteins involved in innate immunity to invading pathogens including TRIF and ZBP1 [428, 439].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [439]
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References 69 · Cited by 237
- Authors
- Maelfait, J., Liverpool, L., Bridgeman, A., Ragan, K. B., Upton, J. W., & Rehwinkel, J.
- Affiliations
- University of Oxford (GB)
- The University of Texas at Austin (US)
- Corresponding author
- Maelfait, Jonathan
- Rehwinkel, Jan
- Venue
- The EMBO Journal
- Published
- 2017-07-17
- Volume
- 36
- Issue
- 17
- Pages
- 2529-2543
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5579359
- OpenAlex
- W2736148366
- Cited by
- 237
- References
- 69
- Citations by year
- 2026: 11 · 2025: 36 · 2024: 36 · 2023: 37 · 2022: 32 · 2021: 23 · 2020: 27 · 2019: 17 · 2018: 14 · 2017: 4
- FWCI
- 7.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The EMBO Journal (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Funders
- Wellcome (100954)
- Cancer Prevention and Research Institute of Texas (R1202)
- Marie Curie Actions
- RCUK|Medical Research Council (MRC)
- European Molecular Biology Organization (EMBOCOFUND2010, GA‐2010‐267146)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- ZBP1, DAI, Z-DNA, necroptosis, viral RNA sensing, endogenous RNA, innate immunity, murine cytomegalovirus, antiviral immunity, inflammatory cell death
- MeSH terms
- Animals, Cytomegalovirus Infections, Cytomegalovirus, Glycoproteins, Mice, Transgenic, Nucleic Acid Conformation, RNA, RNA-Binding Proteins, Apoptosis, NIH 3T3 Cells, Mice
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