Thaneas PrabakaranAnne TroldborgSarinya KumpunyaIsara AleeEmilija MarinkovićSamuel J. WindrossRamya NandakumarRyo NaritaBao cun ZhangMikkel CarstensenPichpisith VejvisithsakulMikkel H.S. MarqvorsenMarie B. IversenChristian K. HolmLars J. ØstergaardFinn Skou PedersenTrairak PisitkunRayk BehrendtPrapaporn PisitkunSøren R. PaludanRamathibodi HospitalAarhus UniversitetChulalongkorn UniversityAarhus UniversitetshospitalTechnische Universität Dresden2022-08-042022-08-042021-04-01EBioMedicine. Vol.66, (2021)235239642-s2.0-85103706447https://repository.li.mahidol.ac.th/handle/123456789/76229Background: 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1016/j.ebiom.2021.103314