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  2. The Golgi-resident protein ACBD3 concentrates STING at ER-Golgi contact sites to drive export from the ER

The Golgi-resident protein ACBD3 concentrates STING at ER-Golgi contact sites to drive export from the ER

  • Cell Rep. 2022 Dec 20;41(12):111868. doi: 10.1016/j.celrep.2022.111868.
Kou Motani 1 Noriko Saito-Tarashima 2 Kohei Nishino 3 Shunya Yamauchi 2 Noriaki Minakawa 2 Hidetaka Kosako 4
Affiliations

Affiliations

  • 1 Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Electronic address: motani@tokushima-u.ac.jp.
  • 2 Graduate School of Pharmaceutical Science, Tokushima University, Shomachi 1-78-1, Tokushima 770-8505, Japan.
  • 3 Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan; Kuramoto Division, Technical Support Department, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
  • 4 Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Abstract

STING, an endoplasmic reticulum (ER)-resident receptor for cyclic di-nucleotides (CDNs), is essential for innate immune responses. Upon CDN binding, STING moves from the ER to the Golgi, where it activates downstream type-I interferon (IFN) signaling. General cargo proteins exit from the ER via concentration at ER exit sites. However, the mechanism of STING concentration is poorly understood. Here, we visualize the ER exit sites of STING by blocking its transport at low temperature or by live-cell imaging with the cell-permeable ligand bis-pivSATE-2'F-c-di-dAMP, which we have developed. After ligand binding, STING forms punctate foci at non-canonical ER exit sites. Unbiased proteomic screens and super-resolution microscopy show that the Golgi-resident protein ACBD3/GCP60 recognizes and concentrates ligand-bound STING at specialized ER-Golgi contact sites. Depletion of ACBD3 impairs STING ER-to-Golgi trafficking and type-I IFN responses. Our results identify the ACBD3-mediated non-canonical cargo concentration system that drives the ER exit of STING.

Keywords

ACBD3; APEX2; CP: Cell biology; CP: Immunology; ER exit site; ER-Golgi contact; ER-to-Golgi trafficking; STING; cyclic di-nucleotide; innate immune signaling; proximity proteomics; type-I interferon.

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