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

EBioMedicine. 2021 Apr;66:103314. doi: 10.1016/j.ebiom.2021.103314. Epub 2021 Apr 2.

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.

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Disease Susceptibility
  • Endoplasmic Reticulum / metabolism*
  • Extracellular Vesicles / metabolism
  • Gene Expression
  • Golgi Apparatus / metabolism*
  • Humans
  • Lupus Erythematosus, Systemic / drug therapy
  • Lupus Erythematosus, Systemic / etiology*
  • Lupus Erythematosus, Systemic / metabolism*
  • Lupus Erythematosus, Systemic / pathology
  • Membrane Proteins / antagonists & inhibitors*
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / metabolism*
  • Protein Transport / drug effects
  • Stromal Interaction Molecule 1 / metabolism*

Substances

  • Membrane Proteins
  • Neoplasm Proteins
  • STIM1 protein, human
  • STING1 protein, human
  • Stromal Interaction Molecule 1