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

Konno, Hiroyasu; Chinn, Iván K.; Hong, Diana N.; Orange, Jordan S.; Lupski, James R.; Mendoza, Alejandra; Pedroza, Luis Alberto; Barber, Glen N.

doi:10.1016/j.celrep.2018.03.115

Cited by 93 publications

(81 citation statements)

References 46 publications

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“…Dengue virus (DENV) NS2B protease cofactor targets cGAS for lysosomal degradation, and subsequently prevents IFN production 78. Intriguingly, cGAS expression is epigenetically silenced by DNA methylation in a variety of human tumors, which results in loss of cGAS signaling 79. Moreover, Ruiz‐Moreno et al have recently reported that small interfering RNA (siRNA) silences cGAS and reduces the production of IFN 80…”

Section: Regulation Of Innate Immune Responsesmentioning

confidence: 99%

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

et al. 2020

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Early detection of infectious nucleic acids released from invading pathogens by the innate immune system is critical for immune defense. Detection of these nucleic acids by host immune sensors and regulation of DNA sensing pathways have been significant interests in the past years. Here, current understandings of evolutionarily conserved DNA sensing cyclic GMP‐AMP (cGAMP) synthase (cGAS) are highlighted. Precise activation and tight regulation of cGAS are vital in appropriate innate immune responses, senescence, tumorigenesis and immunotherapy, and autoimmunity. Hence, substantial insights into cytosolic DNA sensing and immunotherapy of indispensable cytosolic sensors have been detailed to extend limited knowledge available thus far. This Review offers a critical, in‐depth understanding of cGAS regulation, cytosolic DNA sensing, and currently established therapeutic approaches of essential cytosolic immune agents for improved human health.

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Section: Regulation Of Innate Immune Responsesmentioning

confidence: 99%

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

et al. 2020

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“…However, substitutions in the amino acid residues 206, 281, and 284 of STING implicated a ligand-independent mechanism of STING activation (Melki et al, 2017). Additionally, a recent study in which whole exome sequencing was performed from a 9-month-old Ecuadorian boy displaying fever and a severe neck abscess revealed he had a missense heterozygous mutation resulting in the STING variant R284S which constitutively activates STING in the absence of CDNs (Konno et al, 2018). Interestingly, the chilblain lupus mutations that result in activation of STING and production of IFN-β are also induced in the absence of CDNs, indicating that other STING-trafficking mechanisms need to be investigated.…”

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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“…Speculatively, these mutations may expedite STING trafficking from the endoplasmic reticulum to the perinuclear region or affect STING protein stability, thereby sustaining STING activity [112]. Hiroyasu Konno et al identified a STING (R284S) as a new gain-of-function mutation which did not require CDNs to augment activity [113]. Taken together, TMEM173 gain-of-function mutations should be screened for as a monogenic cause of this broad spectrum of diseases.…”

Section: Sting and Autoimmune Diseasementioning

confidence: 99%

STING modulators: Predictive significance in drug discovery

Cui

Zhang

Cen

et al. 2019

European Journal of Medicinal Chemistry

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a b s t r a c tCyclic guanosine monophosphateeadenosine monophosphate synthase (cGAS) d stimulator of interferon genes (STING) signaling pathway plays the critical role in the immune response to DNA. Pharmacological modulation of the STING pathway has been well characterized both from structural and functional perspectives, which paves the way for the drug design of small modulators by medicinal chemists. Here, we outline recent progress in studies on the STING pathway, the structure and biological function of STING, the STING related disease, as well as the rationale and progress in the development of STING modulators. Our review demonstrates that STING is a promising drug target, and providing clues for the discovery of novel STING agonists and antagonists for the potential treatment of various disease including microbial infectious diseases, cancer, and autoimmune disease.

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

Cited by 93 publications

References 46 publications

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

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

STING modulators: Predictive significance in drug discovery

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