Reference - Detail
| RRC ID | 86866 |
|---|---|
| Author | Negishi H, Wada Y, Shirasaki Y, Hayashi T, Kubota Y, Iwasaki T, Kurosawa M, Ban T, Muto D, Suenaga Y, Kojima T, Matsuda Y, Irish SL, Dodo K, Suzuki T, Yamagishi M, Temizoz B, Yoshimori A, Kanai C, Nagasaki Y, Ohmuraya M, Tamura T, Iwama A, Inada T, Kuroda E, Kobiyama K, Toyama-Sorimachi N, Takekawa M, Coban C, Ishii KJ. |
| Title | cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis. |
| Journal | Nat Commun |
| Abstract |
Self-DNA triggers cGAS-STING-mediated type I interferon (IFN-I) to induce both protective and pathogenic immune responses; however, how self-DNA activates the cytosolic cGAS-STING pathway remains unclear. Here we show that the cGAS/STING/IFN-I axis is activated by self-DNA via a process termed 'nucleocytosis', in which nuclear DNA is extracted from dying cells by macrophages. Mechanistically, lysosomal malfunction, via both proton loss and palmitoyl-protein thioesterase 1 (PPT1) inhibition, triggers cell death and calreticulin accumulation in the nuclei. Live-cell imaging of secretion activity reveals that macrophages access the calreticulin-enriched nuclei of dying cells and extract DNA for cGAS-STING activation. Consistent with these findings, PPT1-targeting cationic amphiphilic drugs induce a cGAS-STING-dependent IFN-I response in vitro and in vivo. Our findings thus identify nucleocytosis as a macrophage function for nuclear DNA extraction and induction of the cGAS/IFN-I axis, and suggest that nucleocytosis-inducing cell death could be a druggable target for treating self-DNA-related inflammatory diseases. |
| Volume | 17(1) |
| Pages | 1658 |
| Published | 2026-2-18 |
| DOI | 10.1038/s41467-026-68839-w |
| PII | 10.1038/s41467-026-68839-w |
| PMID | 41708603 |
| PMC | PMC12917151 |
| MeSH | Animals Calreticulin / metabolism Cell Death Cell Nucleus* / metabolism Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase DNA* / immunology DNA* / isolation & purification DNA* / metabolism Humans Interferon Type I* / immunology Interferon Type I* / metabolism Lysosomes / metabolism Macrophages / immunology Macrophages / metabolism Membrane Proteins / genetics Membrane Proteins / metabolism Mice Mice, Inbred C57BL Mice, Knockout Nucleotidyltransferases* / genetics Nucleotidyltransferases* / metabolism RAW 264.7 Cells STING Protein Signal Transduction |
| IF | 12.121 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | News |
| Total number of mentions | 15 |
| Altmetric score changes over past 6months | 52.0 |
| Resource | |
| Mice | RBRC10761 |