A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology

Prabakaran, Thaneas; Troldborg, Anne; Kumpunya, Sarinya; Alee, Isara; Marinković, Emilija; Windross, Samuel J.; Nandakumar, Ramya; Narita, Ryo; Zhang, Bao‐cun; Gjelstrup, Mikkel Carstensen; Vejvisithsakul, Pichpisith Pierre; Marqvorsen, Mikkel H. S.; Iversen, Marie B.; Holm, Christian K.; Østergaard, Lars; Pedersen, Finn Skou; Pisitkun, Trairak; Behrendt, Rayk; Pisitkun, Prapaporn; Paludan, Søren R.

doi:10.1016/j.ebiom.2021.103314

Cited by 48 publications

(39 citation statements)

References 73 publications

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“…Accordingly, loss of Cgas on the lupus-prone MRL/Fas.lpr background resulted in increased proteinuria and cellular infiltration in the kidney 121 . By contrast, a pro-inflammatory effect of STING activation was reported to drive lupus pathology in FcgR2b −/− mice 96 , 122 . Administration of the ISD017 peptide, which blocks STING trafficking from the ER, improved glomerular pathology scores and reduced IgG deposition in the kidney, which suggested that STING-targeted therapeutics might be useful in lupus nephritis 122 .…”

Section: Cgas–sting In Diseasementioning

confidence: 94%

“…By contrast, a pro-inflammatory effect of STING activation was reported to drive lupus pathology in FcgR2b −/− mice 96 , 122 . Administration of the ISD017 peptide, which blocks STING trafficking from the ER, improved glomerular pathology scores and reduced IgG deposition in the kidney, which suggested that STING-targeted therapeutics might be useful in lupus nephritis 122 . The opposing findings in these studies suggest that the roles of cGAS and STING in autoimmune kidney diseases are complex and likely model dependent.…”

Section: Cgas–sting In Diseasementioning

confidence: 94%

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Role of the cGAS–STING pathway in systemic and organ-specific diseases

2022

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Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.

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Section: Cgas–sting In Diseasementioning

confidence: 94%

Section: Cgas–sting In Diseasementioning

confidence: 94%

Role of the cGAS–STING pathway in systemic and organ-specific diseases

2022

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“…Mutations in STIM1 cause severe immune deficiency in humans 35. STIM1 is a potential lupus therapeutic target 36…”

Section: Resultsmentioning

confidence: 99%

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

et al. 2022

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ObjectiveGenome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis.MethodsWe built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches.ResultsTWAS identified 171 genes for SLE (p<1.0×10–5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10–8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10–9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression.ConclusionsCell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

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“…On the other hand, STIM1, which negatively regulates STING by retaining it at the endoplasmic reticulum, was slightly reduced in pSS monocytes. Targeting STIM1 by an influenza-A-derived peptide has been reported to inhibit IFN-I production in an in vitro culture of SLE PBMCs [ 11 ]. Thus, altered balances between positive and negative regulators could potentially alter the sensitivity of the STING pathway in pSS monocytes.…”

Section: Discussionmentioning

confidence: 99%

Hyperresponsive cytosolic DNA-sensing pathway in monocytes from primary Sjögren’s syndrome

Huijser¹,

Bodewes²,

Lourens³

et al. 2022

Rheumatology

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Objectives Cytosolic DNA-sensing pathway stimulation prompts type I IFN (IFN-I) production, but its role in systemic IFN-I pathway activation in primary SS (pSS) is poorly studied. Here, we investigate the responsiveness of pSS monocytes and plasmacytoid dendritic cells (pDCs) to STING activation in relation to systemic IFN-I pathway activation and compare this to SLE. Methods Expression of DNA-sensing receptors cGAS, IFI16, ZBP-1 and DDX41, signalling molecules STING, TBK1 and IRF3, positive and negative STING regulators, and IFN-I-stimulated genes MxA, IFI44, IFI44L, IFIT1, and IFIT3 was analysed in whole blood, CD14+ monocytes, pDCs, and salivary glands by RT-PCR, monocyte RNA-sequencing data, flow cytometry and immunohistochemical staining. Peripheral blood mononuclear cells (PBMCs) from pSS, SLE and healthy controls (HC) were stimulated with STING-agonist 2’3’-cGAMP. STING phopshorylation (pSTING) and intracellular IFNα were evaluated using flow cytometry. Results STING activation induced a significantly higher proportion of IFNα-producing monocytes—but not pDCs—in both IFN-low and IFN-high pSS compared with HC PBMCs. Additionally, a trend towards more pSTING+ monocytes was observed in pSS and SLE, most pronounced in IFN-high patients. Positive STING regulators TRIM38, TRIM56, USP18 and SENP7 were significantly higher expressed in pSS than HC monocytes, while the dual-function STING regulator RNF26 was downregulated in pSS monocytes. STING was expressed in mononuclear infiltrates and ductal epithelium in pSS salivary glands. STING stimulation induced pSTING and IFNα in pSS and SLE pDCs. Conclusion pSS monocytes and pDCs are hyperresponsive to stimulation of the STING pathway, which was not restricted to patients with IFN-I pathway activation.

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A STING antagonist modulating the interaction with STIM1 blocks ER-to-Golgi trafficking and inhibits lupus pathology

Cited by 48 publications

References 73 publications

Role of the cGAS–STING pathway in systemic and organ-specific diseases

Role of the cGAS–STING pathway in systemic and organ-specific diseases

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

Hyperresponsive cytosolic DNA-sensing pathway in monocytes from primary Sjögren’s syndrome

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