死細胞の核からDNAを抽出し、免疫応答を惹起～ヌクレオサイトーシスの発見～

2026-02-19 東京大学

ヌクレオサイトーシスによるI型IFN産生の概略図

<関連情報>

• https://www.ims.u-tokyo.ac.jp/imsut/jp/about/press/page_00377.html
• https://www.nature.com/articles/s41467-026-68839-w

核球症を介して死にかけている細胞から核DNAを抽出することによるcGAS-IFN-I応答 cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis

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,… Ken J. Ishii
Nature Communications  Published:18 February 2026
DOI:https://doi.org/10.1038/s41467-026-68839-w

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.