TY - JOUR

T1 - A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology

AU - Prabakaran, Thaneas

AU - Troldborg, Anne

AU - Kumpunya, Sarinya

AU - Alee, Isara

AU - Marinković, Emilija

AU - Windross, Samuel J

AU - Nandakumar, Ramya

AU - Narita, Ryo

AU - Zhang, Bao-Cun

AU - Carstensen, Mikkel

AU - Vejvisithsakul, Pichpisith

AU - Marqvorsen, Mikkel H S

AU - Iversen, Marie B

AU - Holm, Christian K

AU - Østergaard, Lars J

AU - Pedersen, Finn Skou

AU - Pisitkun, Trairak

AU - Behrendt, Rayk

AU - Pisitkun, Prapaporn

AU - Paludan, Søren R

N1 - Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

PY - 2021/6

Y1 - 2021/6

N2 - 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.

AB - 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.

KW - Immunomodulatory therapy

KW - Inflammation

KW - Innate immunity

KW - Lupus

KW - STING

KW - Type I interferon

UR - http://www.scopus.com/inward/record.url?scp=85103706447&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2021.103314

DO - 10.1016/j.ebiom.2021.103314

M3 - Journal article

C2 - 33813142

VL - 66

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 103314

ER -