A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology.

Abstract

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:

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:

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:

These data hold promise for beneficial use of STING-targeting therapy in lupus.

FUNDING:

The Novo Nordisk Foundation, The European Research Council, The Lundbeck Foundation, European Union under the Horizon 2020 Research, Deutsche Forschungsgemeinschaft, Chulalongkorn University.

• Authors: Thaneas Prabakaran, Anne Troldborg, Sarinya Kumpunya, Isara Alee, Emilija Marinković, Samuel J Windross, Ramya Nandakumar, Ryo Narita, Bao-Cun Zhang, Mikkel Carstensen, Pichpisith Vejvisithsakul, Mikkel H S Marqvorsen, Marie B Iversen, Christian K Holm, Lars J Østergaard, Finn Skou Pedersen, Trairak Pisitkun, Rayk Behrendt, Prapaporn Pisitkun, Søren R Paludan
• Journal: EBioMedicine (EBioMedicine) Vol. 66 Pg. 103314 (Apr 2021) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 33813142 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Membrane Proteins
• Neoplasm Proteins
• STIM1 protein, human
• STING1 protein, human
• Stromal Interaction Molecule 1

Topics

• 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, etiology, metabolism, pathology)
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Mice, Knockout
• Neoplasm Proteins (metabolism)
• Protein Transport (drug effects)
• Stromal Interaction Molecule 1 (metabolism)