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

Melki, Isabelle; Rose, Y; Uggenti, Carolina; Eyck, Lien Van; Frémond, Marie-Louise; Kitabayashi, Naoki; Rice, Gillian I.; Jenkinson, Emma; Boulai, Anaïs; Jeremiah, Nadia; Gattorno, Marco; Volpi, Stefano; Sacco, Oliviero; Terheggen-Lagro, Suzanne; Tiddens, Harm A.W.M.; Meyts, Isabelle; Morren, Marie‐Anne; Haes, Petra De; Wouters, Carine; Legius, Eric; Corveleyn, Anniek; Rieux-Laucat, Frédéric; Bodemer, Christine; Callebaut, Isabelle; Rodero, Mathieu P; Crow, Yanick J.

doi:10.1016/j.jaci.2016.10.031

Cited by 164 publications

(151 citation statements)

References 33 publications

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“…However, reports of a patient exhibiting a mutation at R284 have been documented (R284G compared with R284S), without any noted lethality. It may thus be possible that the serine substitution has a more dramatic effect in vivo for reasons that remain to be fully clarified (Melki et al, 2017). This may help explain the clinical condition associated with STING (R284S) expression compared with the known SAVI-associated mutations, which do not commonly cause death in newborn infants (Liu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Inflammatory disease caused by STING overactivity has also been shown to occur in patients with mutations in the ADAR and ribonuclease H2 enzyme complex. (Crow et al, 2015; Mackenzie et al, 2016; Melki et al,2017; Pokatayev et al, 2016; Rice et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

“…In addition, evidence indicates that inflammatory disease can be caused by germline missense mutations in the coding region of the STING gene itself (V147L/M, N154S, V155M, C206Y, R281Q, R284G, and S102P/F279L), which exert a gain-of-func-tion phenotype referred to as STING-associated vasculopathy with onset in infancy (SAVI) (Clarke et al, 2016; Fre´mond et al, 2016; Jeremiah et al, 2014; Liu et al, 2014; Melki et al, 2017;Picard et al, 2016; Seo et al, 2017). This disease causes skin lesions, rashes, and interstitial lung disease in children.…”

Section: Introductionmentioning

confidence: 99%

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Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

et al. 2018

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The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial orself-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of auto- inflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype. Control of the Unc-51-like autophagy activating kinase 1 (ULK1) pathway, which has previously been shown to influence STING function, was potently able to suppress STING (R284S) activity to alleviate cytokine production. Our findings add to the growing list of inflammatory syndromes associated with spontaneous STING signaling and provide a therapeutic strategy for the treatment of STING-induced inflammatory disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

et al. 2018

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“…The NF-κB and IFN pathways are also intimately linked, with a number of sensors leading to activation of both pathways. In the case of SAVI, literature to date suggests that the IFN pathway is dysregulated in this syndrome [16,17], but whether these two pathways are actually uncoupled in the case of an overactive STING in vivo is unclear. Breeding mutant STING mice to Irf3 −/− mice did not rescue the inflammatory phenotype, raising questions, at least in the murine model, of the role of IFN regulatory transcription factor (IRF) 3 in the inflammation associated with SAVI [18].…”

Section: Classificationmentioning

confidence: 99%

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

Moghaddas

Masters

2018

Clinical Science

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Monogenic autoinflammatory disorders are an increasingly heterogeneous group of conditions characterised by innate immune dysregulation. Improved genetic sequencing in recent years has led not only to the discovery of a plethora of conditions considered to be ‘autoinflammatory’, but also the broadening of the clinical and immunological phenotypic spectra seen in these disorders. This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models. Furthermore, the use of the term ‘autoinflammatory’ is discussed in relation to disorders that cross the innate and adaptive immune divide. The utilisation of next-generation sequencing (NGS) in this population is examined, as are potential in vivo and in vitro methods of modelling to determine pathogenicity of novel genetic findings. Finally, areas where our understanding can be improved are highlighted, such as phenotypic variability and genotype–phenotype correlations, with the aim of identifying areas of future research.

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“…To date, more than 20 patients from multiple pedigrees have been reported with gain-of-function mutations in TMEM173 46,4748495051525354 . Most of the mutations encode amino acid substitutions located close to the dimerization site of STING, and in fact two recombinant mutants (p.N154S and p.V155M) were reported to form a stable homodimer 46 .…”

Section: Type I Interferonopathiesmentioning

confidence: 99%

Genomics, Biology, and Human Illness

Oda

Kastner

2017

Rheumatic Disease Clinics of North America

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SYNOPSIS The monogenic autoinflammatory diseases are a group of illnesses with prominent rheumatic manifestations that are characterized by genetically-determined recurrent sterile inflammation, and are thus inborn errors of innate immunity. Molecular targeted therapies against inflammatory cytokines such as IL-1 and TNF and intracellular cytokine signaling pathways have proven effective in many cases. Emerging next generation sequencing technologies have accelerated the identification of previously unreported genes causing autoinflammatory diseases. In this review we will cover several of the prominent recent advances in the field of autoinflammatory diseases, including gene discoveries, the elucidation of new pathogenic mechanisms, and the development of effective targeted therapies.

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

Abstract: 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.

Cited by 164 publications

References 33 publications

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

Genomics, Biology, and Human Illness

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