期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 140, 期 2, 页码 543-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.10.031
关键词
Stimulator of interferon genes (STING); TMEM173 interferon; type I interferonopathy; STING-associated vasculopathy with onset in infancy
资金
- European Research Council [GA 309449]
- National Research Agency (France) [ANR-10-IAHU-01]
- Imagine Institute (France)
- Research Foundation Flanders (FWO)
- Telethon (Italy) [GGP15241]
- National Research Agency (France) under the Investments for the Future'' program [ANR-10-IAHU-01]
- Telethon, Italy [GGP15241A]
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.
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