Homeostatic regulation of STING by retrograde membrane traffic to the ER

Kojiro Mukai, Emari Ogawa, Rei Uematsu, Yoshihiko Kuchitsu, Fumika Kiku, Takefumi Uemura, Satoshi Waguri, Takehiro Suzuki, Naoshi Dohmae, Hiroyuki Arai, Anthony K. Shum and Tomohiko Taguchi ()
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Kojiro Mukai: Tohoku University
Emari Ogawa: University of Tokyo
Rei Uematsu: University of Tokyo
Yoshihiko Kuchitsu: Tohoku University
Fumika Kiku: University of Tokyo
Takefumi Uemura: Fukushima Medical University School of Medicine
Satoshi Waguri: Fukushima Medical University School of Medicine
Takehiro Suzuki: RIKEN Center for Sustainable Resource Science
Naoshi Dohmae: RIKEN Center for Sustainable Resource Science
Hiroyuki Arai: University of Tokyo
Anthony K. Shum: University of California San Francisco
Tomohiko Taguchi: Tohoku University

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER). Mutation of the COPA gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease known as COPA syndrome. The molecular mechanism by which the impaired retrograde transport results in autoinflammation remains poorly understood. Here we report that STING, an innate immunity protein, is a cargo of the retrograde membrane transport. In the presence of the disease-causative α-COP variants, STING cannot be retrieved back to the ER from the Golgi. The forced Golgi residency of STING results in the cGAS-independent and palmitoylation-dependent activation of the STING downstream signaling pathway. Surf4, a protein that circulates between the ER/ ER-Golgi intermediate compartment/ Golgi, binds STING and α-COP, and mediates the retrograde transport of STING to the ER. The STING/Surf4/α-COP complex is disrupted in the presence of the disease-causative α-COP variant. We also find that the STING ligand cGAMP impairs the formation of the STING/Surf4/α-COP complex. Our results suggest a homeostatic regulation of STING at the resting state by retrograde membrane traffic and provide insights into the pathogenesis of COPA syndrome.

Date: 2021
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DOI: 10.1038/s41467-020-20234-9

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