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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Thaneas Prabakaran
  • Anne Troldborg
  • Sarinya Kumpunya, Chulalongkorn Univ, Chulalongkorn University, Dept Geol
  • ,
  • Isara Alee, Chulalongkorn Univ, Chulalongkorn University, Dept Geol
  • ,
  • Emilija Marinković, Technical University Dresden
  • ,
  • Samuel J Windross
  • Ramya Nandakumar
  • ,
  • Ryo Narita
  • Bao-Cun Zhang, Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus University, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • ,
  • Mikkel Carstensen
  • ,
  • Pichpisith Vejvisithsakul, Department of Medicine, Epidemiology Section, Institute for Clinical and Translational Research, Baylor Medical College, One Baylor Plaza, MS: BCM451, Suite 100D, Houston, TX, 77030-3411, USA., Ramathibodi Hospital, Mahidol University, Bangkok University
  • ,
  • Mikkel H S Marqvorsen
  • Marie B Iversen
  • Christian K Holm
  • Lars J Østergaard
  • Finn Skou Pedersen
  • Trairak Pisitkun, Center of Excellence in Systems Biology, Research Affairs of ISC, Shiraz, Chulalongkorn Univ, Chulalongkorn University, Dept Geol, Bangkok University
  • ,
  • Rayk Behrendt, Technical University Dresden
  • ,
  • Prapaporn Pisitkun, Department of Medicine, Epidemiology Section, Institute for Clinical and Translational Research, Baylor Medical College, One Baylor Plaza, MS: BCM451, Suite 100D, Houston, TX, 77030-3411, USA., Ramathibodi Hospital, Mahidol University, Bangkok University, Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany., Clinical Immunology, Adult and Paediatric Rheumatology Department, National Institute of Rheumatology and Physiotherapy, Budapest, Hungary.
  • ,
  • Søren R Paludan

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 languageEnglish
JournalEBioMedicine
Volume66
Pages (from-to)103314
DOIs
Publication statusE-pub ahead of print - 1 Apr 2021

Bibliographical note

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

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