A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING

  • Nat Commun. 2026 May 27;17(1):4602. doi: 10.1038/s41467-026-72828-4.
Tsumugi Shoji  1 ,  Ayumi Shinojima  1 ,  Takuma Kishimoto  1 ,  Kanako Sato  1 ,  Nana Ikegami  1 ,  Eisuke Yumoto  1 ,  Ruri Shindo  1 ,  Yasunori Uchida  1 ,  Satoshi Kusumi  2 ,  Daisuke Koga  3 ,  Eiji Yamamoto  4 ,  Yoshinori Hirano  5 ,  Ryo Ogino  6 ,  Hirofumi Shibata  6 ,  Kazushi Izawa  6 ,  Takahiro Yasumi  6 ,  Ryota Sato  7 ,  Jun Nakayama  8 ,  Shigeki Higashiyama  8 ,  Junya Hasegawa  9 ,  Hiroaki Kajiho  10 ,  Takehiko Sasaki  10 ,  Yoshihiko Kuchitsu  11 ,  Tomohiko Taguchi  12
Affiliations
  • 1. Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Miyagi, Japan.
  • 2. Department of Morphological Sciences, Kagoshima University, Kagoshima, Japan.
  • 3. Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical University, Hokkaido, Japan.
  • 4. Department of System Design Engineering, Keio University, Kanagawa, Japan.
  • 5. Graduate School of Science and Technology, Keio University, Kanagawa, Japan.
  • 6. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 7. Synergy Institute for Futuristic Mucosal Vaccine Research and Development, Chiba University, Chiba, Japan.
  • 8. Department of Oncogenesis and Growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka, Japan.
  • 9. Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
  • 10. Medical Research Laboratory, Institute of Science Tokyo, Tokyo, Japan.
  • 11. Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Miyagi, Japan. [email protected].
  • 12. Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Miyagi, Japan. [email protected].
PMID: 42203786 DOI: 10.1038/s41467-026-72828-4
Abstract

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.

Products