A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING
Stimulator of interferon genes (STING) is critical for the type I interferon responses to pathogen- or self-derived cytosolic DNA. STING signalling is terminated by ESCRT-driven lysosomal microautophagy. How STING is directly encapsulated by lysosomes has not yet been understood. Here we show that two lysosomal components, a phosphoinositide PI(3,5)P2 and CHMP4B (a subunit of ESCRT-III subcomplex) are essential for STING encapsulation by lysosomes. Liposome sedimentation assay reveals that CHMP4B binds to PI(3,5)P2. The forced recruitment of the catalytic core of Pikfyve (a lipid kinase generating PI(3,5)P2) to early endosomes, recruits a fraction of CHMP4B to early endosomes. CHMP4B mutant, defective in the binding to PI(3,5)P2, cannot restore the microautophagic degradation of STING or the resolution of the STING signalling in cells depleted of Chmp4b. Our results reveal a molecular mechanism that terminates innate immune signalling at the lysosomal membrane. Inhibition of Pikfyve, a kinase generating PI(3,5)P2, abolishes CHMP4B (an ESCRT-III subunit) recruitment to lysosomes, and leads to an accumulation of STING vesicles and sustained signaling. Our results reveal a lysosomal PI(3,5)P2/CHMP4B axis that terminates innate immune signaling.
Authors
- Yoshihiko Kuchitsu (ORCID: https://orcid.org/0000-0003-0422-8056)
- Tsumugi Shoji
- Satoshi Kusumi (ORCID: https://orcid.org/0000-0002-4776-2956)
- Takahiro Yasumi (ORCID: https://orcid.org/0000-0003-3257-5071)
- Hiroaki Kajiho (ORCID: https://orcid.org/0000-0001-6376-7629)
- Ruri Shindo
- Jun Nakayama (ORCID: https://orcid.org/0000-0001-8844-4295)
- Junya Hasegawa (ORCID: https://orcid.org/0000-0003-1216-7468)
- Ayumi Shinojima
- Daisuke Koga (ORCID: https://orcid.org/0000-0002-2792-7207)
- Kazushi Izawa (ORCID: https://orcid.org/0000-0003-1080-0936)
- Takehiko Sasaki (ORCID: https://orcid.org/0000-0003-1837-3748)
- Eisuke Yumoto
- Takuma Kishimoto (ORCID: https://orcid.org/0000-0002-2367-1523)
- Shigeki Higashiyama (ORCID: https://orcid.org/0000-0002-2417-3921)
- Ryota Sato
- Y. Uchida (ORCID: https://orcid.org/0009-0004-2563-2861)
- Ryo Ogino
- Tomohiko Taguchi (ORCID: https://orcid.org/0000-0003-0464-6370)
- Nana Ikegami
- Hirofumi Shibata
- Eiji Yamamoto (ORCID: https://orcid.org/0000-0002-8813-5297)
- Yoshinori Hirano (ORCID: https://orcid.org/0000-0001-8219-7991)
- Kanako Sato
Institutions
- Kagoshima University (JP)
- Asahikawa Medical University (JP)
- Chiba University (JP)
- Tohoku University (JP)
- Keio University (JP)
- Kyoto University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Osaka International Cancer Institute (JP)
- Kitasato University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-27
- DOI
- https://doi.org/10.1038/s41467-026-72828-4
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science
- Division for Interdisciplinary Advanced Research and Education, Tohoku University
- Core Research for Evolutional Science and Technology
- Precursory Research for Embryonic Science and Technology