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

• Published in: Cell reports (Cambridge) Vol. 41; no. 12; p. 111868
• Main Authors: Motani, Kou, Saito-Tarashima, Noriko, Nishino, Kohei, Yamauchi, Shunya, Minakawa, Noriaki, Kosako, Hidetaka
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.12.2022
• Subjects: ACBD3; APEX2; cyclic di-nucleotide; Endoplasmic Reticulum - metabolism; ER exit site; ER-Golgi contact; ER-to-Golgi trafficking; Golgi Apparatus - metabolism; innate immune signaling; Interferon Type I - metabolism; Ligands; Membrane Proteins - metabolism; Protein Transport - physiology; Proteomics; proximity proteomics; STING; type-I interferon; CP: Immunology; ER exit site; innate immune signaling; CP: Cell biology; proximity proteomics; STING; APEX2; type-I interferon; ACBD3; ER-to-Golgi trafficking; ER-Golgi contact; cyclic di-nucleotide
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111868

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. [Display omitted] •STING is concentrated at non-canonical ER exit sites upon ligand binding•Proteomic screens identify ACBD3 as a component of STING ER exit sites•ACBD3 forms a bridging complex with ligand-bound STING at the ER-Golgi interface•Depletion of ACBD3 inhibits STING transport from the ER to the Golgi Motani et al. describe how the endoplasmic reticulum (ER)-resident protein STING exits from the ER to the Golgi upon ligand binding. The Golgi-resident protein ACBD3 captures ligand-bound STING at specific ER-Golgi contact sites, which enables selective and efficient transport of STING.