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A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING
by
Higashiyama, Shigeki
, Uchida, Yasunori
, Yamamoto, Eiji
, Shoji, Tsumugi
, Shindo, Ruri
, Koga, Daisuke
, Ogino, Ryo
, Yasumi, Takahiro
, Shinojima, Ayumi
, Taguchi, Tomohiko
, Hirano, Yoshinori
, Izawa, Kazushi
, Kuchitsu, Yoshihiko
, Hasegawa, Junya
, Kishimoto, Takuma
, Ikegami, Nana
, Sato, Ryota
, Shibata, Hirofumi
, Kajiho, Hiroaki
, Kusumi, Satoshi
, Nakayama, Jun
, Yumoto, Eisuke
, Sato, Kanako
, Sasaki, Takehiko
in
13
/ 14/1
/ 14/19
/ 49
/ 631/250/262/2106
/ 631/80/39
/ 631/80/474/1624
/ Degradation
/ Encapsulation
/ Endosomes
/ Humanities and Social Sciences
/ Interferon
/ Kinases
/ Lipid kinase
/ Lipids
/ Lysosomes
/ Molecular modelling
/ multidisciplinary
/ Protease inhibitors
/ Proteins
/ Science
/ Science (multidisciplinary)
/ Stimulators
2026
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A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING
by
Higashiyama, Shigeki
, Uchida, Yasunori
, Yamamoto, Eiji
, Shoji, Tsumugi
, Shindo, Ruri
, Koga, Daisuke
, Ogino, Ryo
, Yasumi, Takahiro
, Shinojima, Ayumi
, Taguchi, Tomohiko
, Hirano, Yoshinori
, Izawa, Kazushi
, Kuchitsu, Yoshihiko
, Hasegawa, Junya
, Kishimoto, Takuma
, Ikegami, Nana
, Sato, Ryota
, Shibata, Hirofumi
, Kajiho, Hiroaki
, Kusumi, Satoshi
, Nakayama, Jun
, Yumoto, Eisuke
, Sato, Kanako
, Sasaki, Takehiko
in
13
/ 14/1
/ 14/19
/ 49
/ 631/250/262/2106
/ 631/80/39
/ 631/80/474/1624
/ Degradation
/ Encapsulation
/ Endosomes
/ Humanities and Social Sciences
/ Interferon
/ Kinases
/ Lipid kinase
/ Lipids
/ Lysosomes
/ Molecular modelling
/ multidisciplinary
/ Protease inhibitors
/ Proteins
/ Science
/ Science (multidisciplinary)
/ Stimulators
2026
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A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING
by
Higashiyama, Shigeki
, Uchida, Yasunori
, Yamamoto, Eiji
, Shoji, Tsumugi
, Shindo, Ruri
, Koga, Daisuke
, Ogino, Ryo
, Yasumi, Takahiro
, Shinojima, Ayumi
, Taguchi, Tomohiko
, Hirano, Yoshinori
, Izawa, Kazushi
, Kuchitsu, Yoshihiko
, Hasegawa, Junya
, Kishimoto, Takuma
, Ikegami, Nana
, Sato, Ryota
, Shibata, Hirofumi
, Kajiho, Hiroaki
, Kusumi, Satoshi
, Nakayama, Jun
, Yumoto, Eisuke
, Sato, Kanako
, Sasaki, Takehiko
in
13
/ 14/1
/ 14/19
/ 49
/ 631/250/262/2106
/ 631/80/39
/ 631/80/474/1624
/ Degradation
/ Encapsulation
/ Endosomes
/ Humanities and Social Sciences
/ Interferon
/ Kinases
/ Lipid kinase
/ Lipids
/ Lysosomes
/ Molecular modelling
/ multidisciplinary
/ Protease inhibitors
/ Proteins
/ Science
/ Science (multidisciplinary)
/ Stimulators
2026
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A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING
Journal Article
A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING
2026
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Overview
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
2
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
2
. The forced recruitment of the catalytic core of Pikfyve (a lipid kinase generating PI(3,5)P
2
) to early endosomes, recruits a fraction of CHMP4B to early endosomes. CHMP4B mutant, defective in the binding to PI(3,5)P
2
, 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.
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