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

Abstract

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.

Mapping of DNA methylation-sensitive cellular processes in gingival and periodontal ligament fibroblasts in the context of periodontal tissue homeostasis

“…Pathway analysis of DAC-induced genes also identified several processes related to interferon signaling and antiviral responses. While the functional consequences of this effect require further research, it should be noted that GF stimulation with bacterial cyclic dinucleotides results in the induction of a similar cluster of interferon signaling effectors, including ISG15 , MX1 , and IFIT1 ( 55 ). Finally, several DAC-inducible genes in GFs overlap with the transcription profiles observed in gingival biopsies from patients with chronic periodontitis.…”

The role of bacterial cyclic di-adenosine monophosphate in the host immune response

“…The roles of c-di-AMP-mediated bacteria and host interaction in the occurrence and development of diseases are yet unclear. In previous investigations, researchers found that c-di-AMP could regulate the gingival epithelial cytokine response and affect critical processes of gingival fibroblasts, playing a substantial role in the pathogenesis of the periodontal disease (Elmanfi et al, 2018(Elmanfi et al, , 2020Onyedibe et al, 2021). More studies are needed to explore the regulatory effect of bacterial c-di-AMP on the immune microenvironment and the underlying mechanisms.…”

Obesity Modifies the Proteomic Profile of the Periodontal Ligament

“…The protein abundance through proteomics enables the identification of the main proteins present in a sample and also differentially abundant proteins in different samples. Lately, proteomic analysis has been used widely in different challenged oral cells, tissues, and fluids, such as enamel [ 17 ], pulp [ 18 , 19 ], dental cementum [ 20 , 21 , 22 ], PDL [ 23 , 24 ], alveolar bone [ 22 ], periodontal ligament cells [ 25 , 26 ], gingival fibroblasts [ 27 ], gingival tissue [ 28 , 29 ], saliva [ 30 ], and gingival crevicular fluid [ 31 ], enabling researchers to better understand biological processes. Therefore, characterizing the PDL protein profile in obesity conditions becomes important in identifying possible biological markers different from those in health conditions.…”