A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology.
Animals
Cell Line
Disease Models, Animal
Disease Susceptibility
Endoplasmic Reticulum
/ metabolism
Extracellular Vesicles
/ metabolism
Gene Expression
Golgi Apparatus
/ metabolism
Humans
Lupus Erythematosus, Systemic
/ drug therapy
Membrane Proteins
/ antagonists & inhibitors
Mice
Mice, Knockout
Neoplasm Proteins
/ metabolism
Protein Transport
/ drug effects
Stromal Interaction Molecule 1
/ metabolism
Immunomodulatory therapy
Inflammation
Innate immunity
Lupus
STING
Type I interferon
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
02
12
2020
revised:
15
03
2021
accepted:
15
03
2021
pubmed:
5
4
2021
medline:
30
11
2021
entrez:
4
4
2021
Statut:
ppublish
Résumé
Nucleic acids are potent stimulators of type I interferon (IFN-I) and antiviral defense, but may also promote pathological inflammation. A range of diseases are characterized by elevated IFN-I, including systemic lupus erythematosus (lupus). The DNA-activated cGAS-STING pathway is a major IFN-I-inducing pathway, and activation of signaling is dependent on trafficking of STING from the ER to the Golgi. Here we used cell culture systems, a mouse lupus model, and material from lupus patients, to explore the mode of action of a STING antagonistic peptide, and its ability to modulate disease processes. We report that the peptide ISD017 selectively inhibits all known down-stream activities of STING, including IFN-I, inflammatory cytokines, autophagy, and apoptosis. ISD017 blocks the essential trafficking of STING from the ER to Golgi through a mechanism dependent on the STING ER retention factor STIM1. Importantly, ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. Finally, ISD017 treatment blocks pathological cytokine responses in cells from lupus patients with elevated IFN-I levels. These data hold promise for beneficial use of STING-targeting therapy in lupus. The Novo Nordisk Foundation, The European Research Council, The Lundbeck Foundation, European Union under the Horizon 2020 Research, Deutsche Forschungsgemeinschaft, Chulalongkorn University.
Sections du résumé
BACKGROUND
BACKGROUND
Nucleic acids are potent stimulators of type I interferon (IFN-I) and antiviral defense, but may also promote pathological inflammation. A range of diseases are characterized by elevated IFN-I, including systemic lupus erythematosus (lupus). The DNA-activated cGAS-STING pathway is a major IFN-I-inducing pathway, and activation of signaling is dependent on trafficking of STING from the ER to the Golgi.
METHODS
METHODS
Here we used cell culture systems, a mouse lupus model, and material from lupus patients, to explore the mode of action of a STING antagonistic peptide, and its ability to modulate disease processes.
FINDINGS
RESULTS
We report that the peptide ISD017 selectively inhibits all known down-stream activities of STING, including IFN-I, inflammatory cytokines, autophagy, and apoptosis. ISD017 blocks the essential trafficking of STING from the ER to Golgi through a mechanism dependent on the STING ER retention factor STIM1. Importantly, ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. Finally, ISD017 treatment blocks pathological cytokine responses in cells from lupus patients with elevated IFN-I levels.
INTERPRETATION
CONCLUSIONS
These data hold promise for beneficial use of STING-targeting therapy in lupus.
FUNDING
BACKGROUND
The Novo Nordisk Foundation, The European Research Council, The Lundbeck Foundation, European Union under the Horizon 2020 Research, Deutsche Forschungsgemeinschaft, Chulalongkorn University.
Identifiants
pubmed: 33813142
pii: S2352-3964(21)00107-9
doi: 10.1016/j.ebiom.2021.103314
pmc: PMC8047499
pii:
doi:
Substances chimiques
Membrane Proteins
0
Neoplasm Proteins
0
STIM1 protein, human
0
STING1 protein, human
0
Stromal Interaction Molecule 1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103314Subventions
Organisme : European Research Council
ID : 786602
Pays : International
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest TP, CKH, LØ, and SRP own shares in ISD Immunotech, which owns the patent for ISD017 (WO2014166502A2). The patent was the patent was issued by CKH. None of the other authors have conflicts to declare.