TY - JOUR T1 - Activation of STING due to COPI-deficiency JF - bioRxiv DO - 10.1101/2020.07.09.194399 SP - 2020.07.09.194399 AU - Annemarie Steiner AU - Katja Hrovat Schaale AU - Ignazia Prigione AU - Dominic De Nardo AU - Laura F. Dagley AU - Chien-Hsiung Yu AU - Pawat Laohamonthonkul AU - Cassandra R. Harapas AU - Michael P. Gantier AU - Marco Gattorno AU - Stefano Volpi AU - Sophia Davidson AU - Seth L. Masters Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/09/2020.07.09.194399.abstract N2 - COPA syndrome is caused by loss-of-function mutations in the COP-α subunit of coatomer protein complex I (COPI), which participates in retrograde vesicular trafficking of proteins from the Golgi to the endoplasmic reticulum (ER). Disease manifests early in life with arthritis, lung pathology, kidney dysfunction and systemic inflammation associated with NF-κB activation and type I interferon (IFNαβ) production. Here, we generated in vitro models for COPA syndrome and interrogated inflammatory signalling pathways via a range of biochemical and molecular biological techniques. Results were confirmed with cell lines in which mutant COPA was overexpressed and with COPA syndrome patient PBMCs. We identified Stimulator of Interferon Genes (STING), as a driver of inflammation in COPA syndrome. Furthermore, we found that genetic deletion of COPG1, another COPI subunit protein, induced NF-κB and type I IFN pathways similar to COPA-deficiency. Finally, we demonstrate that in vitro, inflammation due to COPA syndrome mutations was ameliorated by treatment with the small molecule STING inhibitor H-151. Therefore, inflammation induced by deletion of COPI subunits in general suggests a link between retrograde trafficking and STING regulation, and this innate immune sensor represents a novel therapeutic target in COPA syndrome.Competing Interest StatementM.G. declares consultancy and speakers fee from Novartis and SOBI. S.L.M. receives funding from IFM therapeutics. The other authors declare no competing financial interests.COPI/IIcoatomer complex I/IICOPAcoatomer complex I subunit A (α)COPBcoatomer complex I subunit B (β)COPEcoatomer complex I subunit E (ε)COPDcoatomer complex I subunit D (δ)COPGcoatomer complex I subunit G (γ)COPZcoatomer complex I subunit Z (ζ)cGAScyclic GMP-AMP-synthaseCXCL10CX-C Motif Chemokine Ligand 10DoxDoxycyclineERendoplasmic reticulumGFPgreen fluorescent proteinIFNinterferonIRF3Interferon regulatory factor 3ISG15interferon stimulated gene 15JAK 1/2Janus kinase 1/2NF-κBnuclear factor kappaNLRP3NOD-like receptor Pyrin Domain Containing 3MAVSmitochondrial antiviral signalling proteinMX1MX Dynamin Like GTPase1PBMCperipheral blood mononuclear cellPKRprotein kinase RPRRpattern recognition receptorSEC13/31/23/24COPII coat complex componentSTAT1signal transducer and activator of transcription 1STINGstimulator of interferon geneSURF4Surfeit protein 4TBK1TANK binding kinase 1TNFtumor necrosis factorUNC93B1Unc-93 Homolog B1, TLR Signalling RegulatorUSP18Ubiquitin specific peptidase18 ER -