A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome.
Animals
Coatomer Protein
/ genetics
Endoplasmic Reticulum
/ metabolism
Fibroblasts
/ metabolism
Gene Knock-In Techniques
Golgi Apparatus
/ metabolism
HEK293 Cells
Homeostasis
/ immunology
Humans
Immune System Diseases
/ genetics
Interferon Type I
/ metabolism
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation, Missense
Protein Transport
/ genetics
Signal Transduction
/ genetics
Syndrome
Transfection
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
02 11 2020
02 11 2020
Historique:
received:
21
05
2020
revised:
07
07
2020
accepted:
08
07
2020
entrez:
30
7
2020
pubmed:
30
7
2020
medline:
11
3
2021
Statut:
ppublish
Résumé
Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi-ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon-driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.
Identifiants
pubmed: 32725126
pii: 151981
doi: 10.1084/jem.20201045
pmc: PMC7596814
pii:
doi:
Substances chimiques
Coatomer Protein
0
Interferon Type I
0
Membrane Proteins
0
STING1 protein, human
0
SURF4 protein, human
0
Sting1 protein, mouse
0
Surf4 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL103453
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL135403
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI137249
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122533
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 Deng et al.
Déclaration de conflit d'intérêts
Disclosures: T. Martinu reported grants from Sanofi and non-financial support from APCBio outside the submitted work. No other disclosures were reported.
Références
J Immunol. 2013 Apr 1;190(7):3289-98
pubmed: 23440417
Cell Host Microbe. 2015 Aug 12;18(2):157-68
pubmed: 26235147
Clin Immunol. 2018 Feb;187:33-36
pubmed: 29030294
J Immunol. 2020 May 1;204(9):2360-2373
pubmed: 32198142
Nature. 2008 Sep 18;455(7211):396-400
pubmed: 18701890
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16357-62
pubmed: 19721001
Bioinformatics. 2013 Nov 1;29(21):2810-1
pubmed: 23958726
Bio Protoc. 2013 Sep 20;3(18):
pubmed: 27376106
Nat Immunol. 2016 May;17(5):565-73
pubmed: 27043411
Am J Respir Cell Mol Biol. 2001 May;24(5):591-8
pubmed: 11350829
Sci Rep. 2017 Sep 19;7(1):11902
pubmed: 28928425
Mol Cell Biol. 2002 Apr;22(7):2111-23
pubmed: 11884599
Eur J Rheumatol. 2019 Aug 20;:1-4
pubmed: 31449490
Nat Immunol. 2019 Feb;20(2):152-162
pubmed: 30643259
Nat Commun. 2016 Jun 21;7:11932
pubmed: 27324217
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Genet. 2015 Jun;47(6):654-60
pubmed: 25894502
Science. 2015 Mar 13;347(6227):aaa2630
pubmed: 25636800
Nat Immunol. 2013 Feb;14(2):179-85
pubmed: 23263557
N Engl J Med. 2014 Aug 7;371(6):507-518
pubmed: 25029335
EMBO J. 2000 Aug 1;19(15):3905-17
pubmed: 10921873
Nucleic Acids Res. 2019 Jan 8;47(D1):D506-D515
pubmed: 30395287
Nature. 2019 Mar;567(7747):262-266
pubmed: 30842662
Immunity. 2011 Sep 23;35(3):426-40
pubmed: 21903422
Elife. 2018 Sep 25;7:
pubmed: 30251625
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Mol Biol Cell. 2008 May;19(5):1976-90
pubmed: 18287528
Cell Rep. 2019 Jan 2;26(1):250-265.e5
pubmed: 30605680
Proteomics. 2018 Jan;18(2):
pubmed: 29251827
Nature. 2018 Jul;559(7713):269-273
pubmed: 29973723
Genome Biol. 2007;8(9):R183
pubmed: 17784955
Annu Rev Immunol. 2019 Apr 26;37:247-267
pubmed: 30633609
ERJ Open Res. 2018 Jun 27;4(2):
pubmed: 29977900
Nat Immunol. 2020 Jan;21(1):17-29
pubmed: 31819255
Nature. 2017 May 25;545(7655):505-509
pubmed: 28514442
Nature. 2018 Jul;559(7715):627-631
pubmed: 30022164