Activated STING in a Vascular and Pulmonary Syndrome

By Yin Liu, A. A. Jesus, B. Marrero, Dan Yang, S. Ramsey, G. Sanchez, K. Tenbrock, H. Wittkowski, O. Jones, H. Kuehn and 42 more. New England Journal of Medicine, 2014

1,198 citations recorded by the source corpus.

BACKGROUND The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-β, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mono-nuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibro-blasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients’ lymphocytes was reduced by JAK inhibitors. CONCLUSIONS STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/3db4d5df90765ceffddf4740ef90840ec783fd1d

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In Immunology

1. Zhijian J. Chen
2. Tuo Li
3. A. Ablasser
4. Xiang Chen
5. Xiao-Dong Li
6. Daxing Gao
7. G. Barber
8. Shizuo Akira

In Molecular Biology

1. Zhijian J. Chen
2. Tuo Li
3. A. Ablasser
4. Xiang Chen
5. S. Tait
6. G. Barber
7. Joel S. Riley

In Oncology

1. Zhijian J. Chen
2. A. Ablasser

Citations in the corpus

• cGAS in action: Expanding roles in immunity and inflammation (2019, background): “This is reflected by gain-of-function mutations within STING, which leads to T cell apoptosis in humans and to severe T cell lymphopenia in mice (37, 38).”
• The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, background): “While accumulation of cytosolic DNA through nuclear DNA damage, loss-of-function mutations of DNA degrading enzymes, or tissue damage leads to autoinflammatory diseases, gain-offunction mutations in STI NG are sufficient to cause an autoinflammatory disorder termed STI NG-associated vasculopathy wit”
• Activation of STING requires palmitoylation at the Golgi (2016, neutral): “Furthermore, mutations in STING are found in patients with an autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI) 19 and more recently in patients with lupus-like syndromes 20 .”
• Mitochondrial DNA in inflammation and immunity (2020, neutral): “Gain-of-function mutations in STING itself lead to an up-regulation of type I interferon responses and lupus-like symptoms in patients [103,104].”
• Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases (2015, background): “Interestingly, patients with gain-of-function mutations in STING also develop lupus-like syndromes; however, these patients also exhibit unique features of vascular and pulmonary inflammation (31, 32).”