TY - JOUR
T1 - Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling
AU - Melki, Isabelle
AU - Rose, Yoann
AU - Uggenti, Carolina
AU - van Eyck, Lien
AU - Frémond, Marie-Louise
AU - Kitabayashi, Naoki
AU - Rice, Gillian I.
AU - Jenkinson, Emma M.
AU - Boulai, Anaïs
AU - Jeremiah, Nadia
AU - Gattorno, Marco
AU - Volpi, Sefano
AU - Sacco, Olivero
AU - Terheggen-Lagro, Suzanne W. J.
AU - Tiddens, Harm A. W. M.
AU - Meyts, Isabelle
AU - Morren, Marie-Anne
AU - de Haes, Petra
AU - Wouters, Carine
AU - Legius, Eric
AU - Corveleyn, Anniek
AU - Rieux-Laucat, Frederic
AU - Bodemer, Christine
AU - Callebaut, Isabelle
AU - Rodero, Mathieu P.
AU - Crow, Yanick J.
PY - 2017
Y1 - 2017
N2 - 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 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
AB - 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 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
U2 - https://doi.org/10.1016/j.jaci.2016.10.031
DO - https://doi.org/10.1016/j.jaci.2016.10.031
M3 - Article
C2 - 28087229
SN - 0091-6749
VL - 140
SP - 543-+
JO - Journal of allergy and clinical immunology
JF - Journal of allergy and clinical immunology
IS - 2
ER -