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

• Main 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
• Format: Article
• Language: English
• Published: Elsevier 2021-04-01
• Series: EBioMedicine
• Subjects: Lupus; STING; Innate immunity; Type I interferon; Inflammation; Immunomodulatory therapy
• Online Access: http://www.sciencedirect.com/science/article/pii/S2352396421001079

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.