Regulating STING in health and disease

Li, Yang; Wilson, Heather L.; Kiss-Tóth, Endre

doi:10.1186/s12950-017-0159-2

Cited by 78 publications

(62 citation statements)

References 223 publications

(271 reference statements)

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“…The binding of STING and TBK1 causes autophosphorylation of TBK1 at Serine-172, which then facilitates the direct phosphorylation of STING at its Serine-366 and Leucine-374 residues by TBK1. Consequently, phosphorylation of STING by TBK1 recruits IRF3 to also be phosphorylated by TBK1 (Li et al, 2017c; Liu et al, 2015a; Tanaka and Chen, 2012). The association of TBK1 with STING facilitates the dsDNA-mediated activation of the NF-κB and IRF3 transcription factors.…”

Section: Intracellular Recognition Of Dnamentioning

confidence: 99%

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Matz

Guzman

Goodman

2019

Nucleic Acid Sensing and Immunity - Part B

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Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe’s genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed.

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Section: Intracellular Recognition Of Dnamentioning

confidence: 99%

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Matz

Guzman

Goodman

2019

Nucleic Acid Sensing and Immunity - Part B

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“…STING has four amino-terminal transmembrane domains spanning the first 136 amino acid residues, followed by the helix α1 at residues 153-177 (8). Helix α1, also known as the dimerization domain, is essential for protein stability, intraprotein interactions and ligand binding (9).…”

Section: Introductionmentioning

confidence: 99%

“…Helix α1, also known as the dimerization domain, is essential for protein stability, intraprotein interactions and ligand binding (9). The CDN binding domain (residues 153-340) is part of the cytoplasmic carboxy-terminus, stretching over residues 138-379 and having multiple phosphorylation and downstream signaling interaction sites (8,10).…”

Section: Introductionmentioning

confidence: 99%

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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“…STING is also involved in modulating innate immune responses against RNA virus infections [7]. Human immunodeficiency virus (HIV), influenza A virus, Sendai virus (SeV), and vesicular stomatitis virus trigger STING signaling dependently and independently of DNA detection [8]. Additionally, STING may be associated with autoimmune diseases, lipid metabolism [8], and tumor development [9].…”

Section: Introductionmentioning

confidence: 99%

“…Human immunodeficiency virus (HIV), influenza A virus, Sendai virus (SeV), and vesicular stomatitis virus trigger STING signaling dependently and independently of DNA detection [8]. Additionally, STING may be associated with autoimmune diseases, lipid metabolism [8], and tumor development [9]. Upon infection with a DNA virus or retrovirus, cGAS recognizes cytosolic viral DNA and causes the production of type-I IFN and the expression of interferon stimulated genes (ISGs) [10].…”

Section: Introductionmentioning

confidence: 99%

Identification and function analysis of canine stimulator of interferon gene (STING)

Zhang

Zhu

et al. 2017

Microbial Pathogenesis

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Stimulator of interferon gene (STING) plays an important role in the cyclic GMP-AMP synthase (cGAS)-mediated activation of type I IFN responses. In this study, we identified and cloned canine STING gene. Full-length STING encodes a 375 amino acid product that shares the highest similarity with feline STING. Highest levels of mRNA of canine STING were detected in the spleen and lungs while the lowest levels in the heart and muscle. Analysis of its cellular localization showed that STING is localizes to the endoplasmic reticulum. STING overexpression induced the IFN response via the IRF3 and NF-κB pathways and up-regulated the expression of ISG15 and viperin. However, knockdown of STING did not inhibit the IFN-β response triggered by poly(dA:dT), poly(I:C), or SeV. Finally, overexpression of STING significantly inhibited the replication of canine influenza virus H3N2. Collectively, our findings indicate that STING is involved in the regulation of the IFN-β pathway in canine.

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Regulating STING in health and disease

Cited by 78 publications

References 223 publications

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Characterization of novel TMEM173 mutation with additive IFIH1 risk allele

Identification and function analysis of canine stimulator of interferon gene (STING)

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