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Homeostatic regulation of STING by retrograde membrane traffic to the ER
Author(s) -
Mukai Kojiro,
Shum Anthony,
Taguchi Tomohiko
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01855
Subject(s) - sting , golgi apparatus , endoplasmic reticulum , copi , microbiology and biotechnology , innate immune system , biology , chemistry , genetics , immune system , secretory pathway , aerospace engineering , engineering
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 retro‐ grade 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 1,2 . 1 K. Mukai et al., Nat Commun 12, (2021). 2 Z. Deng,Z. Chong, C. S. Law, K. Mukai et al., J Exp Med 217, e20201045 (2020).