Publication: A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology
6
Issued Date
2021-04-01
Resource Type
ISSN
23523964
Other identifier(s)
2-s2.0-85103706447
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
EBioMedicine. Vol.66, (2021)
Suggested Citation
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 A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology. EBioMedicine. Vol.66, (2021). doi:10.1016/j.ebiom.2021.103314 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/76229
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology
Author(s)
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
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
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.