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

Isabelle Melki, Yoann Rose, Carolina Uggenti, Lien Van Eyck, Marie-louise Frémond, Naoki Kitabayashi, Gillian I. Rice, Emma M. Jenkinson, Anaïs Boulai, Nadia Jeremiah, Marco Gattorno, Sefano Volpi, Olivero Sacco, Suzanne W.j. Terheggen-lagro, Harm A.w.m. Tiddens, Isabelle Meyts, Marie-anne Morren, Petra De Haes, Carine Wouters, Eric LegiusAnniek Corveleyn, Frederic Rieux-laucat, Christine Bodemer, Isabelle Callebaut, Mathieu P. Rodero, Yanick J. Crow

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)543-552.e5
JournalJournal of Allergy and Clinical Immunology
Issue number2
Early online date10 Jan 2017
Publication statusPublished - 1 Aug 2017


  • Adolescent
  • Adult
  • Amino Acid Substitution
  • Child
  • Female
  • HEK293 Cells
  • Humans
  • Inflammation/genetics
  • Interferon Type I/genetics
  • Male
  • Membrane Proteins/genetics
  • Mutation
  • STAT1 Transcription Factor/metabolism
  • Signal Transduction


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