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

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A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology. / Prabakaran, Thaneas; Troldborg, Anne; Kumpunya, Sarinya et al.

I: EBioMedicine, Bind 66, 103314, 06.2021.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{f66656e122194699af88c59342a9d704,
title = "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.",
keywords = "Immunomodulatory therapy, Inflammation, Innate immunity, Lupus, STING, Type I interferon",
author = "Thaneas Prabakaran and Anne Troldborg and Sarinya Kumpunya and Isara Alee and Emilija Marinkovi{\'c} and Windross, {Samuel J} and Ramya Nandakumar and Ryo Narita and Bao-Cun Zhang and Mikkel Carstensen and Pichpisith Vejvisithsakul and Marqvorsen, {Mikkel H S} and Iversen, {Marie B} and Holm, {Christian K} and {\O}stergaard, {Lars J} and Pedersen, {Finn Skou} and Trairak Pisitkun and Rayk Behrendt and Prapaporn Pisitkun and Paludan, {S{\o}ren R}",
note = "Copyright {\textcopyright} 2021 The Author(s). Published by Elsevier B.V. All rights reserved.",
year = "2021",
month = jun,
doi = "10.1016/j.ebiom.2021.103314",
language = "English",
volume = "66",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier",

}

RIS

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 -