cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis
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.
Authors
- Atsushi Yoshimori (ORCID: https://orcid.org/0000-0003-3206-5143)
- Yoshitaka Shirasaki (ORCID: https://orcid.org/0000-0002-3808-1630)
- Cevayir Coban (ORCID: https://orcid.org/0000-0002-4467-7799)
- Yusuke Suenaga (ORCID: https://orcid.org/0000-0001-6902-5386)
- Atsushi Iwama (ORCID: https://orcid.org/0000-0001-9410-8992)
- Daisuke Muto
- Toshifumi Inada (ORCID: https://orcid.org/0000-0002-2695-588X)
- Chisato Kanai (ORCID: https://orcid.org/0000-0001-9160-7737)
- Noriko Toyama‐Sorimachi (ORCID: https://orcid.org/0000-0003-3474-0456)
- Kosuke Dodo (ORCID: https://orcid.org/0000-0001-6008-2915)
- Hideo Negishi
- Mutsuhiro Takekawa (ORCID: https://orcid.org/0000-0002-8027-3847)
- Tomoya Hayashi (ORCID: https://orcid.org/0000-0003-3189-6463)
- Tatsuma Ban (ORCID: https://orcid.org/0000-0001-9517-9661)
- Yoji NAGASAKI
- Yusuke Wada
- T. Kojima
- Burcu Temizoz
- Ken J. Ishii
- Tomio Iwasaki
- Kouji Kobiyama
- Mai Yamagishi
- Yuzuki Matsuda
- Etsushi Kuroda
- Toru Suzuki
- Tomohiko Tamura
- Mina Kurosawa
- Yuji Kubota
- Masaki Ohmuraya
- Sean Lord Irish
Institutions
- Pioneer (United States) (US)
- Chiba University (JP)
- Yokohama City University Medical Center (JP)
- National Kyushu Medical Center (JP)
- University of California San Diego (US)
- Quantitative BioSciences (US)
- RIKEN Center for Sustainable Resource Science (JP)
- Chiba Cancer Center (JP)
- Saitama International Medical Center (JP)
- Japan Community Healthcare Organization (JP)
- Shanghai Cell Therapy Research Institute (CN)
- Hitachi (Japan) (JP)
- The University of Tokyo (JP)
- Hyogo University (JP)
- Yokohama City University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-18
- DOI
- https://doi.org/10.1038/s41467-026-68839-w
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Hokkaido University
- Joint Research Centre
- Japan Society for the Promotion of Science
- Institute of Medical Science, University of Tokyo
- Core Research for Evolutional Science and Technology