On taking the STING out of immune activation

Banete, Andra; Seaver, Kyle; Bakshi, Devyani; Gee, Katrina; Basta, Sameh

doi:10.1002/jlb.2mir0917-383r

Cited by 18 publications

(15 citation statements)

References 91 publications

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“…STING can recognize CDNs and cyclic nucleic acids either directly or bound to cytosolic DNA sensors including cGAS, nuclear resident IFI16 (IFN‐inducible protein 16), and helicase DDX41 (DExD/H‐box) . However, the discussion of the detailed mechanism of the cGAS‐STING signaling pathway is beyond the scope of the present article and discussed elsewhere …”

Section: Cgas‐sting Signaling Pathway and Sensing The Cytosolic Dsdnamentioning

confidence: 93%

A STING to inflammation and autoimmunity

Kumar

2019

Journal of Leukocyte Biology

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Various intracellular pattern recognition receptors (PRRs) recognize cytosolic pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Cyclic GMP-AMP synthase (cGAS), a cytosolic PRR, recognizes cytosolic nucleic acids including dsDNAs. The recognition of dsDNA by cGAS generates cyclic GMP-AMP (GAMP). The cGAMP is then recognized by STING generating type 1 IFNs and NF-B-mediated generation of proinflammatory cytokines and molecules. Thus, cGAS-STING signaling mediated recognition of cytosolic dsDNA causing the induction of type 1 IFNs plays a crucial role in innate immunity against cytosolic pathogens, PAMPs, and DAMPs. The overactivation of this system may lead to the development of autoinflammation and autoimmune diseases. The article opens with the introduction of different PRRs involved in the intracellular recognition of dsDNA and gives a brief introduction of cGAS-STING signaling. The second section briefly describes cGAS as intracellular PRR required to recognize intracellular nucleic acids (dsDNA and CDNs) and the formation of cGAMP. The cGAMP acts as a second messenger to activate STING-and TANK-binding kinase 1-mediated generation of type 1 IFNs and the activation of NF-B. The third section of the article describes the role of cGAS-STING signaling in the induction of autoinflammation and various autoimmune diseases. The subsequent fourth section describes both chemical compounds developed and the endogenous negative regulators of cGAS-STING signaling required for its regulation. Therapeutic targeting of cGAS-STING signaling could offer new ways to treat inflammatory and autoimmune diseases. K E Y W O R D S

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Section: Cgas‐sting Signaling Pathway and Sensing The Cytosolic Dsdnamentioning

confidence: 93%

A STING to inflammation and autoimmunity

Kumar

2019

Journal of Leukocyte Biology

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“…Not long after the initial steps in the characterisation of the IFNβ enhanceosome were made, also the first viral proteins targeting its assembly were noticed [ 175 , 176 ]. Today, a long list of viral factors targeting every step from the stimulation of PRRs by nucleic acids, to induction of transcription factor activation, to activity of IFN, through to the stimulation and activity of ISGs are known, and the list still grows [ 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 ]. The central role of IRF3 in this pathway makes it an attractive target for viral evasion.…”

Section: Saboteurs Of the Main Act—viral Modulation Of Activated Imentioning

confidence: 99%

Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression

Schwanke

Stempel

Brinkmann

2020

Viruses

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The type I interferon (IFN) response is a principal component of our immune system that allows to counter a viral attack immediately upon viral entry into host cells. Upon engagement of aberrantly localised nucleic acids, germline-encoded pattern recognition receptors convey their find via a signalling cascade to prompt kinase-mediated activation of a specific set of five transcription factors. Within the nucleus, the coordinated interaction of these dimeric transcription factors with coactivators and the basal RNA transcription machinery is required to access the gene encoding the type I IFN IFNβ (IFNB1). Virus-induced release of IFNβ then induces the antiviral state of the system and mediates further mechanisms for defence. Due to its key role during the induction of the initial IFN response, the activity of the transcription factor interferon regulatory factor 3 (IRF3) is tightly regulated by the host and fiercely targeted by viral proteins at all conceivable levels. In this review, we will revisit the steps enabling the trans-activating potential of IRF3 after its activation and the subsequent assembly of the multi-protein complex at the IFNβ enhancer that controls gene expression. Further, we will inspect the regulatory mechanisms of these steps imposed by the host cell and present the manifold strategies viruses have evolved to intervene with IFNβ transcription downstream of IRF3 activation in order to secure establishment of a productive infection.

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“…Type-I interferons (IFNs) play a cardinal role in the pathogenesis of SS [ 44 , 45 ]. Upon activation, cytosolic DNA sensors interact with the stimulator of interferon genes (STING) protein, and the ensuing activation of STING causes increased expression of type-I IFN-α [ 46 ]. IL-17 also has a pivotal involvement in SS where overexpression in mice models triggers an enhanced inflammatory response accompanied by salivary impairment [ 47 ].…”

Section: Defective Localization Of Aqps In the Salivary Glands Of mentioning

confidence: 99%

Involvement of Aquaporins in the Pathogenesis, Diagnosis and Treatment of Sjögren’s Syndrome

Soyfoo

Chivasso

Perret

et al. 2018

IJMS

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Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands resulting in diminished production of saliva and tears. The pathophysiology of SS has not yet been fully deciphered. Classically it has been postulated that sicca symptoms in SS patients are a double step process whereby lymphocytic infiltration of lacrimal and salivary glands (SG) is followed by epithelial cell destruction resulting in keratoconjunctivitis sicca and xerostomia. Recent advances in the field of the pathophysiology of SS have brought in new players, such as aquaporins (AQPs) and anti AQPs autoantibodies that could explain underlying mechanistic processes and unveil new pathophysiological pathways offering a deeper understanding of the disease. In this review, we delineate the link between the AQP and SS, focusing on salivary glands, and discuss the role of AQPs in the treatment of SS-induced xerostomia.

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On taking the STING out of immune activation

Cited by 18 publications

References 91 publications

A STING to inflammation and autoimmunity

A STING to inflammation and autoimmunity

Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression

Involvement of Aquaporins in the Pathogenesis, Diagnosis and Treatment of Sjögren’s Syndrome

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