Isabelle Melki1, Yoann Rose2, Carolina Uggenti2, Lien Van Eyck3, Marie-Louise Frémond4, Naoki Kitabayashi2, Gillian I Rice5, Emma M Jenkinson5, Anaïs Boulai2, Nadia Jeremiah6, Marco Gattorno7, Stefano Volpi7, Olivero Sacco8, Suzanne W J Terheggen-Lagro9, Harm A W M Tiddens10, Isabelle Meyts11, Marie-Anne Morren12, Petra De Haes13, Carine Wouters14, Eric Legius15, Anniek Corveleyn16, Frederic Rieux-Laucat6, Christine Bodemer17, Isabelle Callebaut18, Mathieu P Rodero2, Yanick J Crow19. 1. INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debré, AP-HP, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. 2. INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France. 3. INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium. 4. INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. 5. Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom. 6. Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmunity, Paris, France. 7. UO Pediatria 2 Reumatologia, G. Gaslini, Genova, Italy. 8. UO Pneumologia, G. Gaslini, Genova, Italy. 9. Department of Paediatric, Pulmonology Emma Children's Hospital AMC DD, Amsterdam, The Netherlands. 10. Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Paediatrics, Respiratory Medicine and Allergology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands. 11. Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium. 12. Department of Dermatology, University Hospitals Leuven, Leuven, Belgium. 13. Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium; Department of Dermatology, University Hospitals Leuven, Leuven, Belgium. 14. Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium. 15. Department of Human Genetics, KU Leuven, Leuven, Belgium; Clinical Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium. 16. Clinical Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium. 17. Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Dermatology Department, National Reference Center for Rare Skin Diseases MAGEC, Hôpital Necker-Enfants Malades, Paris, France. 18. CNRS UMR7590, Sorbonne Université, Université Pierre et Marie Curie-Paris6-MNHN-IRD-IUC, Paris, France. 19. INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom. Electronic address: yanickcrow@mac.com.
Abstract
BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI). OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. METHODS: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed. RESULTS: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. CONCLUSIONS: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.
BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI). OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. METHODS: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed. RESULTS: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. CONCLUSIONS: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.
Authors: Mona Motwani; Sudesh Pawaria; Jennifer Bernier; Stephanie Moses; Kate Henry; Terry Fang; Linda Burkly; Ann Marshak-Rothstein; Katherine A Fitzgerald Journal: Proc Natl Acad Sci U S A Date: 2019-04-03 Impact factor: 11.205
Authors: Wei Liu; Gloria B Kim; Nathan A Krump; Yuqi Zhou; James L Riley; Jianxin You Journal: Proc Natl Acad Sci U S A Date: 2020-06-01 Impact factor: 11.205