Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling

• Published in: Journal of allergy and clinical immunology Vol. 140; no. 2; pp. 543 - 552.e5
• Main Authors: Melki, Isabelle, MD, Rose, Yoann, BSc, Uggenti, Carolina, PhD, Van Eyck, Lien, MD, Frémond, Marie-Louise, MD, Kitabayashi, Naoki, BSc, Rice, Gillian I., PhD, Jenkinson, Emma M., PhD, Boulai, Anaïs, BSc, Jeremiah, Nadia, PhD, Gattorno, Marco, MD, Volpi, Sefano, MD, PhD, Sacco, Olivero, MD, Terheggen-Lagro, Suzanne W.J., MD, Tiddens, Harm A.W.M., MD, PhD, Meyts, Isabelle, MD, PhD, Morren, Marie-Anne, MD, De Haes, Petra, MD, PhD, Wouters, Carine, MD, PhD, Legius, Eric, MD, PhD, Corveleyn, Anniek, PhD, Rieux-Laucat, Frederic, PhD, Bodemer, Christine, MD, PhD, Callebaut, Isabelle, PhD, Rodero, Mathieu P., PhD, Crow, Yanick J., MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2017; Elsevier Limited; Elsevier
• Subjects: Adolescent; Adult; Allergy and Immunology; Amino Acid Substitution; Amino acids; Child; Cytometry; Deoxyribonucleic acid; Disease; DNA; Enzyme inhibitors; Female; Genetic analysis; HEK293 Cells; Humans; Inflammation - genetics; Interferon; Interferon Type I - genetics; Interferon Type I - metabolism; Janus kinase; Kinases; Lesions; Life Sciences; Lung diseases; Male; Membrane fusion; Membrane Proteins - genetics; Mutagenesis; Mutation; Pathology; Phosphorylation; Proteins; RNA viruses; Signal Transduction; Skin diseases; STAT1 Transcription Factor - metabolism; Stimulator of interferon genes (STING); STING-associated vasculopathy with onset in infancy; Structural analysis; TMEM173; type I interferonopathy; Vascular diseases; Viruses; Transmembrane protein 173; Stimulator of interferon genes; PDB; TBK1; Stimulator of interferon genes (STING); ExAC; Exome Aggregation Consortium; Protein Data Bank; WT; 2′3′-Cyclic GMP-AMP; C-terminal cyclic dinucleotide-binding domain; STAT1; SAVI; Signal transducer and activator of transcription 1; GMP; TANK-binding kinase; TMEM173; interferon; ER; Wild-type; HEK; 3D; CTD; cGAMP; Three-dimensional; IRF3; Interferon regulatory factor 3; Cyclic guanosine monophosphate; type I interferonopathy; STING; STING-associated vasculopathy with onset in infancy; Human embryonic kidney; Endoplasmic reticulum
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.10.031

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.