Tsumugi Shoji, Ayumi Shinojima, Takuma Kishimoto, Kanako Sato, Nana Ikegami, Eisuke Yumoto, Ruri Shindo, Y. 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
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.