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

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