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<p>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.</p>

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cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月18日

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  • Hideo Negishi,
  • Yusuke Wada,
  • Yoshitaka Shirasaki,
  • Tomoya Hayashi,
  • Yuji Kubota,
  • Tomio Iwasaki,
  • Mina Kurosawa,
  • Tatsuma Ban,
  • Daisuke Muto,
  • Yusuke Suenaga,
  • Taichi Kojima,
  • Yuzuki Matsuda,
  • Sean Lord Irish,
  • Kosuke Dodo,
  • Toru Suzuki,
  • Mai Yamagishi,
  • Burcu Temizoz,
  • Atsushi Yoshimori,
  • Chisato Kanai,
  • Yoji Nagasaki,
  • Masaki Ohmuraya,
  • Tomohiko Tamura,
  • Atsushi Iwama,
  • Toshifumi Inada,
  • Etsushi Kuroda,
  • Kouji Kobiyama,
  • Noriko Toyama-Sorimachi,
  • Mutsuhiro Takekawa,
  • Cevayir Coban,
  • Ken J. Ishii

摘要

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.