Activation of STING due to COPI-deficiency
Annemarie Steiner [MSc]; Katja Hrovat Schaale [PhD]; Ignazia Prigione [PhD]; Dominic De Nardo [PhD]; Laura F. Dagley [PhD]; Chien-Hsiung Yu [PhD]; Pawat Laohamonthonkul; Cassandra R. Harapas [BSc]; Michael P. Gantier [PhD]; Marco Gattorno [MD]; Stefano Volpi [MD, PhD]; Sophia Davidson [PhD]; Seth L. Masters [PhD]
Show abstract
COPA syndrome is caused by loss-of-function mutations in the COP- 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-{kappa}B activation and type I interferon (IFN{beta}) 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-{kappa}B 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.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Integrated signaling and transcriptome analysis reveals Src-family kinase individualities and novel pathways controlled by their constitutive activity 96%
- The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection 95%
- Dysregulated immune responses in COVID-19 patients correlating with disease severity and invasive oxygen requirements 94%
Similar papers in this journal
Similar papers in this journal
- HDAC6/aggresome processing pathway importance for inflammasome formation is context dependent 96%
- Downregulation of PIK3IP1/TrIP on T cells is controlled by TCR signal strength, PKC, and metalloprotease-mediated cleavage 95%
- Glycosyltransferase POMGNT1 deficiency affects N-cadherin-mediated cell-cell adhesion 95%
Similar papers in this journal
- Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity 94%
- Polypyrimidine Tract Binding Protein 1 regulates the activation of mouse CD8 T cells 94%
- Levamisole suppresses activation and proliferation of human T cells by the induction of a p53-dependent DNA damage response 93%
Similar papers in this journal
- LRRC8A regulates hypotonicity-induced NLRP3 inflammasome activation 95%
- Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory programming and continual clearance of apoptotic cells 94%
- Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.