Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations
Top Cited Papers
Open Access
- 17 November 2014
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 124 (12), 5516-5520
- https://doi.org/10.1172/jci79100
Abstract
Innate immunity to viral infection involves induction of the type I IFN response; however, dysfunctional regulation of this pathway leads to inappropriate inflammation. Here, we evaluated a nonconsanguineous family of mixed European descent, with 4 members affected by systemic inflammatory and autoimmune conditions, including lupus, with variable clinical expression. We identified a germline dominant gain-of-function mutation in TMEM173, which encodes stimulator of type I IFN gene (STING), in the affected individuals. STING is a key signaling molecule in cytosolic DNA-sensing pathways, and STING activation normally requires dimerization, which is induced by 2'3' cyclic GMP-AMP (cGAMP) produced by the cGAMP synthase in response to cytosolic DNA. Structural modeling supported constitutive activation of the mutant STING protein based on stabilized dimerization. In agreement with the model predictions, we found that the STING mutant spontaneously localizes in the Golgi of patient fibroblasts and is constitutively active in the absence of exogenous 2'3'-cGAMP in vitro. Accordingly, we observed elevated serum IFN activity and a type I IFN signature in peripheral blood from affected family members. These findings highlight the key role of STING in activating both the innate and adaptive immune responses and implicate aberrant STING activation in features of human lupus.Keywords
This publication has 21 references indexed in Scilit:
- Activated STING in a Vascular and Pulmonary SyndromeNew England Journal of Medicine, 2014
- Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signalingNature Genetics, 2014
- Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control studyThe Lancet Neurology, 2013
- Cyclic Dinucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune SignalingCell, 2013
- STING Recognition of Cytoplasmic DNA Instigates Cellular DefenseMolecular Cell, 2013
- Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon PathwayScience, 2013
- Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNAScience, 2013
- Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signatureNature Genetics, 2012
- Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune systemNature Structural & Molecular Biology, 2012
- Structural Analysis of the STING Adaptor Protein Reveals a Hydrophobic Dimer Interface and Mode of Cyclic di-GMP BindingImmunity, 2012