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

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

doi:10.1016/j.ebiom.2021.103314

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

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^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

43 Citations (Scopus)

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.

Original language	English
Article number	103314
Journal	EBioMedicine
Volume	66
Number of pages	13
DOIs	https://doi.org/10.1016/j.ebiom.2021.103314
Publication status	Published - Jun 2021

Keywords

Immunomodulatory therapy
Inflammation
Innate immunity
Lupus
STING
Type I interferon

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Prabakaran, T., Troldborg, A., Kumpunya, S., Alee, I., Marinković, E., Windross, S. J., Nandakumar, R., Narita, R., Zhang, B.-C., Carstensen, M., Vejvisithsakul, P., Marqvorsen, M. H. S., Iversen, M. B., Holm, C. K., Østergaard, L. J., Pedersen, F. S., Pisitkun, T., Behrendt, R., Pisitkun, P., & Paludan, S. R. (2021). A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology. EBioMedicine, 66, Article 103314. https://doi.org/10.1016/j.ebiom.2021.103314

@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}",

year = "2021",

month = jun,

doi = "10.1016/j.ebiom.2021.103314",

language = "English",

volume = "66",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

}

Prabakaran, T, Troldborg, A, Kumpunya, S, Alee, I, Marinković, E, Windross, SJ, Nandakumar, R, Narita, R , Zhang, B-C , Carstensen, M, Vejvisithsakul, P, Marqvorsen, MHS , Iversen, MB , Holm, CK , Østergaard, LJ, Pedersen, FS, Pisitkun, T, Behrendt, R, Pisitkun, P & Paludan, SR 2021, 'A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology', EBioMedicine, vol. 66, 103314. https://doi.org/10.1016/j.ebiom.2021.103314

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.
In: EBioMedicine, Vol. 66, 103314, 06.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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

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

SN - 2352-3964

VL - 66

JO - EBioMedicine

JF - EBioMedicine

M1 - 103314

ER -

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

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Keywords

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