STING-associated vasculopathy develops independently of IRF3 in mice

Warner, James D.; Irizarry-Caro, Ricardo A.; Bennion, Brock G.; Ai, Teresa L.; Smith, Amber M.; Miner, Cathrine A.; Sakai, Tomomi; Gonugunta, Vijay K.; Wu, Jianjun; Platt, Derek J.; Yan, Nan; Miner, Jonathan J.

doi:10.1084/jem.20171351

Cited by 160 publications

(223 citation statements)

References 37 publications

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“…Interestingly, IRF3 phosphorylation remained at similarly low levels in all studied combinations and their single counterparts, while N154S showed markedly elevated phosphorylation (Figure 2E). In concordance with our data, IRF3 independent disease development was recently reported in a STING N153S mouse model (31), demonstrating the involvement and activation of multiple pathways in STING-associated disease.…”

Section: G207e Mutation In Sting Constitutively Activates Ifn-β Statsupporting

confidence: 93%

Characterization of novel TMEM173 mutation with additive IFIH1 risk allele

Keskitalo

Haapaniemi

Einarsdottir

et al. 2018

Preprint

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TMEM173 encodes for STING that is a transmembrane protein activated by pathogen or self-derived cytosolic nucleic acids causing its translocation from ER to Golgi, and further to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms causing the poor phenotypegenotype correlation are presently unclear. Here we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and STING-associated vasculopathy with onset in infancy (SAVI) -features; livedo reticularis, nasal septum perforation, facial erythema, bacterial infections and skin vasculitis. Single residue polymorphisms in TMEM173 and an IFIH1 T946 risk allele modify disease presentation in the affected multigeneration family, explaining the varying clinical phenotypes. The G207E mutation causes constitutive activation of inflammation-related pathways in HEK cells, as well as aberrant interferon signature and inflammasome activation in patient PBMCs. Protein-protein interactions further propose impaired cellular trafficking of G207E mutant STING. These findings reveal the molecular landscape of STING and highlight the complex additive effects on the phenotype.BRIEF SUMMARYNovel gain-of-function mutation in TMEM173, associated with single residue polymorphisms in TMEM173 and IFIH1, causes a distinct clinical phenotype with some shared features of SAVI.

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Section: G207e Mutation In Sting Constitutively Activates Ifn-β Statsupporting

confidence: 93%

Characterization of novel TMEM173 mutation with additive IFIH1 risk allele

Keskitalo

Haapaniemi

Einarsdottir

et al. 2018

Preprint

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“…Warner et al 41 recently described another model of STING GOF, the N153S model, corresponding to the N154S mutation in patients with SAVI. These mice had an inflammatory disease with pulmonary inflammation in the absence of fibrosis and skin inflammation associated with an immune deficiency, including T-cell lymphopenia.…”

Section: Discussionmentioning

confidence: 99%

Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice

Bouis

Kirstetter

Arbogast

et al. 2019

Journal of Allergy and Clinical Immunology

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“…The etiology of SAVI is a gain of function (GOF) mutant in STING which leads to constitutive STING activation without CDNs stimulation (166). Currently, several mutant amino acids residues have been found in or close to the dimerization domain (V155M, N154S, G166E, V147L, and V147M) (64,166,168,170), as well as R284G, R284S, R281Q, and C206Y in the cGAMP-binding domain (171).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

“…The inhibitory role of cGAS-STING in inflammation is also attributed to its apoptosis-triggering role. In some subtypes of SAVI and mouse models, apoptosis of blood-vessel endothelial cells or bronchial epithelial cells and leucopenia can be observed (especially T-cell lymphopenia) (166,169,170). When the STING signal is stimulated, apoptosis occurs more frequently in normal or cancerous T cells (119).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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STING-associated vasculopathy develops independently of IRF3 in mice

Abstract: Warner et al. show that knock-in mice expressing a human disease–associated STING mutation spontaneously develop inflammatory lung and skin disease, hypercytokinemia, and T cell cytopenia, which occurs independently of IRF3.

Cited by 160 publications

References 37 publications

Characterization of novel TMEM173 mutation with additive IFIH1 risk allele

Characterization of novel TMEM173 mutation with additive IFIH1 risk allele

Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

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