Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol

Haruka Kemmoku, Kanoko Takahashi, Kojiro Mukai, Toshiki Mori, Koichiro M. Hirosawa, Fumika Kiku, Yasunori Uchida, Yoshihiko Kuchitsu, Yu Nishioka, Masaaki Sawa, Takuma Kishimoto, Kazuma Tanaka, Yasunari Yokota, Hiroyuki Arai, Kenichi G. N. Suzuki () and Tomohiko Taguchi ()
Additional contact information
Haruka Kemmoku: Tohoku University
Kanoko Takahashi: Tohoku University
Kojiro Mukai: Tohoku University
Toshiki Mori: Gifu University
Koichiro M. Hirosawa: Gifu University
Fumika Kiku: University of Tokyo
Yasunori Uchida: Tohoku University
Yoshihiko Kuchitsu: Tohoku University
Yu Nishioka: Carna Biosciences, Inc.
Masaaki Sawa: Carna Biosciences, Inc.
Takuma Kishimoto: Hokkaido University Graduate School of Life Science
Kazuma Tanaka: Hokkaido University Graduate School of Life Science
Yasunari Yokota: Gifu University
Hiroyuki Arai: University of Tokyo
Kenichi G. N. Suzuki: Gifu University
Tomohiko Taguchi: Tohoku University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Stimulator of interferon genes (STING) is critical for the type I interferon response to pathogen- or self-derived DNA in the cytosol. STING may function as a scaffold to activate TANK-binding kinase 1 (TBK1), but direct cellular evidence remains lacking. Here we show, using single-molecule imaging of STING with enhanced time resolutions down to 5 ms, that STING becomes clustered at the trans-Golgi network (about 20 STING molecules per cluster). The clustering requires STING palmitoylation and the Golgi lipid order defined by cholesterol. Single-molecule imaging of TBK1 reveals that STING clustering enhances the association with TBK1. We thus provide quantitative proof-of-principle for the signaling STING scaffold, reveal the mechanistic role of STING palmitoylation in the STING activation, and resolve the long-standing question of the requirement of STING translocation for triggering the innate immune signaling.

Date: 2024
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DOI: 10.1038/s41467-023-44317-5

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