Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling

Chang, Denis; Whiteley, Aaron T.; Gwilt, Katlynn Bugda; Lencer, Wayne I.; Mekalanos, John J.; Thiagarajah, Jay R.

doi:10.1073/pnas.2015919117

Cited by 17 publications

(13 citation statements)

References 51 publications

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“…H151, a specific inhibitor for STING and RU.521, a specific inhibitor for cGAS were added 1 h previous infection of THP-1 cells at 10 μM and 10 μg/ml, respectively, selected according to the previously published results ( Chang et al., 2020 ; Hayden et al., 2020 ). Then, cells were infected with rNiV-eGFP or rMeV-edmH-eGFP and incubated for 24 or 48 h at 37°C with 5% CO2.…”

Section: Methodsmentioning

confidence: 99%

Activation of cGAS/STING pathway upon paramyxovirus infection

et al. 2021

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Summary During inflammatory diseases, cancer, and infection, the cGAS/STING pathway is known to recognize foreign or self-DNA in the cytosol and activate an innate immune response. Here, we report that negative-strand RNA paramyxoviruses, Nipah virus (NiV), and measles virus (MeV), can also trigger the cGAS/STING axis. Although mice deficient for MyD88, TRIF, and MAVS still moderately control NiV infection when compared with wild-type mice, additional STING deficiency resulted in 100% lethality, suggesting synergistic roles of these pathways in host protection. Moreover, deletion of cGAS or STING resulted in decreased type I interferon production with enhanced paramyxoviral infection in both human and murine cells. Finally, the phosphorylation and ubiquitination of STING, observed during viral infections, confirmed the activation of cGAS/STING pathway by NiV and MeV. Our data suggest that cGAS/STING activation is critical in controlling paramyxovirus infection and possibly represents attractive targets to develop countermeasures against severe disease induced by these pathogens.

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Section: Methodsmentioning

confidence: 99%

Activation of cGAS/STING pathway upon paramyxovirus infection

et al. 2021

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“…We profiled the expression levels of the proteomes in c-di-AMP and c-di-GMP treated HGFs. While c-di-AMP and c-di-GMP are negatively charged and hence difficult to get into cells, earlier studies by us and also by others have shown that at high enough concentrations (such as 100 µM) some of the CDN get into the cell to affect the signaling pathway [ 14 , 15 , 23 ]. We also chose a 24 h time period for cell exposure to CDNs to mimic chronic infection whereby mammalian cells are constantly exposed to bacterial PAMPs for extended period.…”

Section: Resultsmentioning

confidence: 99%

Global proteomics of fibroblast cells treated with bacterial cyclic dinucleotides, c-di-GMP and c-di-AMP

Onyedibe

Elmanfi

Aryal

et al. 2021

Journal of Oral Microbiology

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Background Constant exposure of human gingival fibroblasts (HGFs) to oral pathogens trigger selective immune responses. Recently, the activation of immune response to cyclic dinucleotides (CDNs) via STING has come to the forefront. Reports show that other proteins outside the STING-TBK1-IRF3 axis respond to CDNs but a global view of impacted proteome in diverse cells is lacking. HGFs are constantly exposed to bacterial-derived cyclic-di-adenosine monophosphate (c-di-AMP) and cyclic-di-guanosine monophosphate (c-di-GMP). AIM To understand the response of HGFs to bacterial-derived CDNs, we carried out a global proteomics analysis of HGFs treated with c-di-AMP or c-di-GMP. Methods The expression levels of several proteins modulated by CDNs were examined. Results Interferon signaling proteins such as Ubiquitin-like protein ISG15 (ISG15), Interferon-induced GTP-binding protein Mx1 (MX1), Interferon-induced protein with tetratricopeptide repeats (IFIT) 1 (IFIT1), and (IFIT3) were significantly upregulated. Interestingly, other pathways not fully characterized to be regulated by CDNs, such as necroptosis signaling, iron homeostasis signaling, protein ubiquitination, EIF2 signaling, sumoylation and nucleotide excision repair pathways were also modulated by the bacterial-derived CDNs. Conclusion This study has added to the increasing appreciation that beyond the regulation of cytokine production via STING, cyclic dinucleotides also broadly affect many critical processes in human cells.

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“…One reason for the preferential localization of CD73 in villus tip enterocytes is to counteract the ATP released by bacteria in the intestinal lumen and thereby control inappropriate immune activation by the host microbiome. Other potential functions may include the metabolism of cyclic dinucleotides to regulate host defense mechanisms at mucosal surfaces, and CD73 may also serve as a source of antimicrobial adenosine to prevent bacterial colonization and infection [68]. CD73 distribution on pericentral hepatocytes in the mammalian liver likely enables the cells to calibrate their metabolic activities under physiological low-oxygen conditions because genetic deletion of hepatocyte CD73 results in metabolic and inflammatory liver injury [29].…”

Section: Cd73 Is Zonally Expressed On Subsets Of Cells Within Epithelial Tissuesmentioning

confidence: 99%

The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)

Alcedo

Bowser

Snider

2021

Trends in Cell Biology

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Purinergic signaling is a fundamental mechanism used by all cells to control their internal activities and interact with the environment. A key component of the purinergic system, the enzyme ecto-5′-nucleotidase (CD73) catalyzes the last step in the extracellular metabolism of ATP to form adenosine. Efforts to harness the therapeutic potential of endogenous adenosine in cancer have culminated in the ongoing clinical development of multiple CD73-targeting antibodies and small-molecule inhibitors. However, recent studies are painting an increasingly complex picture of CD73 mRNA and protein regulation and function in cellular homeostasis, physiological adaptation, and disease development. This review discusses the latest conceptual and methodological advances that are helping to unravel the complexity of this important enzyme that was identified nearly 90 years ago. CD73 is an integral component of the purinergic systemCells produce and consume ATP in a tightly regulated manner to ensure optimal organismal function. In addition to being used as fuel for essential activities within the cell, ATP is also released outside of the cell, where the sequential removal of its phosphate groups results in the formation of the nucleoside adenosine. Extracellular ATP and adenosine, together with associated synthetic and catabolic enzymes, receptors, and transporters, are part of the evolutionarily conserved purinergic system which links cellular metabolism to a myriad of other processes, including proliferation, differentiation, and cell death [1].

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Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling

Cited by 17 publications

References 51 publications

Activation of cGAS/STING pathway upon paramyxovirus infection

Activation of cGAS/STING pathway upon paramyxovirus infection

Global proteomics of fibroblast cells treated with bacterial cyclic dinucleotides, c-di-GMP and c-di-AMP

The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)

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