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<p>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)P<sub>2</sub> 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)P<sub>2</sub>. The forced recruitment of the catalytic core of Pikfyve (a lipid kinase generating PI(3,5)P<sub>2</sub>) to early endosomes, recruits a fraction of CHMP4B to early endosomes. CHMP4B mutant, defective in the binding to PI(3,5)P<sub>2</sub>, cannot restore the microautophagic degradation of STING or the resolution of the STING signalling in cells depleted of <i>Chmp4b</i>. Our results reveal a molecular mechanism that terminates innate immune signalling at the lysosomal membrane.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月27日

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  • Tsumugi Shoji,
  • Ayumi Shinojima,
  • Takuma Kishimoto,
  • Kanako Sato,
  • Nana Ikegami,
  • Eisuke Yumoto,
  • Ruri Shindo,
  • Yasunori Uchida,
  • Satoshi Kusumi,
  • Daisuke Koga,
  • Eiji Yamamoto,
  • Yoshinori Hirano,
  • Ryo Ogino,
  • Hirofumi Shibata,
  • Kazushi Izawa,
  • Takahiro Yasumi,
  • Ryota Sato,
  • Jun Nakayama,
  • Shigeki Higashiyama,
  • Junya Hasegawa,
  • Hiroaki Kajiho,
  • Takehiko Sasaki,
  • Yoshihiko Kuchitsu,
  • Tomohiko Taguchi

摘要

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.