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Lysine acetylation is a frequently occurring post-translational modification (PTM), emerging as an important metabolic regulatory mechanism in prokaryotes. This process is achieved enzymatically by the protein acetyltransferase (KAT) to specifically transfer the acetyl group, or non-enzymatically by direct intermediates (acetyl phosphate or acetyl-CoA). Although lysine acetylation modification of glucosyltransferases (Gtfs), the important virulence factor in Streptococcus mutans , was reported in our previous study, the KAT has not been identified. Here, we believe that the KAT ActG can acetylate Gtfs in the enzymatic mechanism. By overexpressing 15 KATs in S . mutans , the synthesized water-insoluble extracellular polysaccharides (EPS) and biofilm biomass were measured, and KAT ( actG ) was identified. The in-frame deletion mutant of actG was constructed to validate the function of actG . The results showed that actG could negatively regulate the water-insoluble EPS synthesis and biofilm formation. We used mass spectrometry (MS) to identify GtfB and GtfC as the possible substrates of ActG. This was also demonstrated by in vitro acetylation assays, indicating that ActG could increase the acetylation levels of GtfB and GtfC enzymatically and decrease their activities. We further found that the expression level of actG in part explained the virulence differences in clinically isolated strains. Moreover, overexpression of actG in S . mutans attenuated its cariogenicity in the rat caries model. Taken together, our study demonstrated that the KAT ActG could induce the acetylation of GtfB and GtfC enzymatically in S . mutans , providing insights into the function of lysine acetylation in bacterial virulence and pathogenicity.

Background Early childhood caries (ECC), particularly severe early childhood caries (S-ECC), remains a prevalent chronic disease, significantly affecting children’s health and quality of life. Despite extensive research, the detailed ecological and metabolic shifts underlying S-ECC pathogenesis are still poorly characterized. Integrating microbial and metabolic profiling of saliva may provide crucial insights and identify novel biomarkers and therapeutic targets. Methods We performed high-throughput 16S rRNA gene sequencing and untargeted metabolomics to comprehensively profile the salivary microbiome and metabolome in children with S-ECC ( n  = 30) compared to caries-free (CF) controls ( n  = 30). Differential microbial taxa and metabolites were identified, and their functional implications were explored through KEGG pathway enrichment analysis. Furthermore, integrated correlation analysis was conducted to uncover interactions between key microbial taxa and metabolites. Results Microbial community analysis revealed significant ecological alterations in the saliva of children with S-ECC, characterized by enrichment of potentially cariogenic taxa, including Rothia , Lautropia , Lactobacillus , Achromobacter , as well as Streptococcus mutans , Prevotella histicola , and Lachnoanaerobaculum saburreum . Conversely, health-associated genera such as Bergeyella and Acinetobacter were more abundant in CF children. Metabolomics identified a total of 4,325 salivary metabolites, among which 1,226 differed significantly between groups. Notably, metabolites involved in amino acid metabolism pathways—phenylalanine, tyrosine, D-amino acids, aminobenzoate, arginine, and proline—were upregulated in S-ECC saliva. Integrated analysis further revealed strong positive correlations between key cariogenic bacteria ( S. mutans , P. histicola , L. saburreum ) and multiple metabolites, including succinic acid, 2-piperidone, D-3-phenyllactic acid, 5-aminovaleric acid, L-malic acid, 2-hydroxypalmitic acid, LPE (16:0), vitamin K1 2,3-epoxide, leucylproline, and L-valine. Conclusions Our findings demonstrate distinct ecological and functional signatures in the salivary microbiome and metabolome associated with S-ECC. The identified microbial and metabolic alterations, particularly in amino acid metabolism, provide novel insights into the pathogenesis of S-ECC and highlight potential biomarkers for early detection and targeted intervention. However, the cross-sectional design and single time-point saliva collection limit the ability to assess longitudinal dynamics. Future longitudinal studies are warranted to track microbial and metabolomic changes during disease progression and intervention.

Post-transcriptional regulation by small RNAs and post-translational modifications (PTM) such as lysine acetylation play fundamental roles in physiological circuits, offering rapid responses to environmental signals with low energy consumption. Yet, the interplay between these regulatory systems remains underexplored. Here, we unveil the cross-talk between sRNAs and lysine acetylation in Streptococcus mutans , a primary cariogenic pathogen known for its potent acidogenic virulence. Through systematic overexpression of sRNAs in S . mutans , we identified sRNA SmsR1 as a critical player in modulating acidogenicity, a key cariogenic virulence feature in S . mutans . Furthermore, combined with the analysis of predicted target mRNA and transcriptome results, potential target genes were identified and experimentally verified. A direct interaction between SmsR1 and 5’-UTR region of pdhC gene was determined by in vitro binding assays. Importantly, we found that overexpression of SmsR1 reduced the expression of pdhC mRNA and increased the intracellular concentration of acetyl-CoA, resulting in global changes in protein acetylation levels. This was verified by acetyl-proteomics in S . mutans , along with an increase in acetylation level and decreased activity of LDH. Our study unravels a novel regulatory paradigm where sRNA bridges post-transcriptional regulation with post-translational modification, underscoring bacterial adeptness in fine-tuning responses to environmental stress.

Dental caries poses a significant challenge to global oral health, driven by microbial dysbiosis within dental biofilms. The pathogenicity of Streptococcus mutans , a major cariogenic bacterium, is closely linked to its ability to adapt to changing environments and cellular stresses. Our investigation into the protein acetylation mechanisms, particularly through the acetyltransferase ActA, reveals a critical pathway by which S. mutans modulates its adaptability to oxidative stress, the dominant stressor within dental biofilms. By elucidating how ActA affects the oxidative stress adaptability and competitiveness of S. mutans through the regulatory axis of ActA-PykF-pyruvate, our findings provide insights into the dynamic interplay between cariogenic and commensal bacteria within dental biofilms. This work emphasizes the significance of protein acetylation in bacterial stress response and competitiveness, opening avenues for the development of novel strategies to maintain oral microbial balance within dental biofilms.

Lysine acetylation, a dynamic regulatory posttranslational modification, remains poorly characterized in bacteria. Hundreds of proteins have been identified to be acetylated in bacteria, with advances made in acetylome analyses. Lysine acetylation, a ubiquitous and dynamic regulatory posttranslational modification (PTM), affects hundreds of proteins across all domains of life. In bacteria, lysine acetylation can be found in many essential pathways, and it is also crucial for bacterial virulence. However, the biological significance of lysine acetylation events to bacterial virulence factors remains poorly characterized. In Streptococcus mutans , the acetylome profiles help identify several lysine acetylation sites of lactate dehydrogenase (LDH), which catalyzes the conversion of pyruvate to lactic acid, causing the deterioration of teeth. We investigated the regulatory mechanism of LDH acetylation and characterized the effect of LDH acetylation on its function. We overexpressed the 15 Gcn5 N -acetyltransferases (GNAT) family members in S. mutans and showed that the acetyltransferase ActA impaired its acidogenicity by acetylating LDH. Additionally, enzymatic acetyltransferase reactions demonstrated that purified ActA could acetylate LDH in vitro , and 10 potential lysine acetylation sites of LDH were identified by mass spectrometry, 70% of which were also detected in vivo . We further demonstrated that the lysine acetylation of LDH inhibited its enzymatic activity, and a subsequent rat caries model showed that ActA impaired the cariogenicity of S. mutans . Collectively, we demonstrated that ActA, the first identified and characterized acetyltransferase in S. mutans , acetylated the LDH enzymatically and inhibited its enzymatic activity, thereby providing a starting point for the further analysis of the biological significance of lysine acetylation in the virulence of S. mutans . IMPORTANCE Lysine acetylation, a dynamic regulatory posttranslational modification, remains poorly characterized in bacteria. Hundreds of proteins have been identified to be acetylated in bacteria, with advances made in acetylome analyses. However, the regulatory mechanisms and functional significance of the majority of these acetylated proteins remain unclear. We analyzed the acetylome profiles of Streptococcus mutans and found that lactate dehydrogenase (LDH) contains several lysine acetylation sites. We also demonstrated that the acetyltransferase ActA, a member of the Gcn5 N -acetyltransferases (GNAT) family in S. mutans , acetylated LDH, inhibited its enzymatic ability to catalyze the conversion of pyruvate to lactic acid, and impaired its cariogenicity in a rat caries model. Therefore, LDH acetylation might be a potential target that can be exploited in the design of novel therapeutics to prevent dental caries.

Dental caries is a biofilm-mediated disease that arises from polymicrobial dysbiosis in dental plaque. Among these microorganisms, plays a prominent role because of its strong capacity to metabolize fermentable carbohydrates into organic acids that drive enamel demineralization. Central to this process is pyruvate, a key metabolic intermediate that connects glycolysis, energy production, biosynthesis, and stress adaptation. Pyruvate metabolism in directs carbon flow into various pathways that contribute to its cariogenic potential, including acidogenesis, biofilm formation, and oxidative stress tolerance. This review explores the multifaceted roles of pyruvate in , emphasizing its involvement in the production of lactate, acetate, formate, and branched-chain amino acids. We also discuss the regulatory mechanisms that control pyruvate metabolism, such as the Pta-Ack pathway, LrgAB-mediated pyruvate transport, and transcriptional regulation by CcpA/CodY. Furthermore, we highlight promising strategies for caries prevention, including the targeting of pyruvate metabolism using natural compounds and metabolic inhibitors. Future research should focus on elucidating the regulatory networks governing pyruvate metabolism, the metabolic byproducts, and the impact of disrupting pyruvate-based metabolic crosstalk in polymicrobial biofilms. Understanding how pyruvate functions as a carrier or precursor metabolite in central carbon metabolism of and its regulation of survival and metabolic processes will have significant implications for caries prevention.

Background. Obesity is a main contributing factor for the development of glucose intolerance and type 2 diabetes mellitus (T2D). Roux-en-Y gastric bypass (RYGB) is believed to be one of the most effective treatments to reduce body weight and improve glucose metabolism. In this study, we sought to explore the underlying mechanisms of weight reduction and insulin resistance improvement after RYGB. Methods. This was a prospective observational study using consecutive samples of 14 obese subjects undergoing bariatric surgery. Main assessments were serum indexes (blood metabolites, glucose-lipid regulating hormones, trimethylamine-N-oxide (TMAO), and lipopolysaccharide-binding protein (LBP), fecal short-chain fatty acids (SCFAs), and gut microbiota. Correlation analysis of the factors changed by RYGB was used to indicate the potential mechanism by which surgery improves insulin resistance. Results. The subjects showed significant improvement on indices of obesity and insulin resistance and a correlated change of gut microbiota components at 1 month, 3 months, and 6 months post-RYGB operation. In particular, the abundance of a counterobese strain, Akkemansia muciniphila, had gradually increased with the postoperative time. Moreover, these changes were negatively correlated to serum levels of LBP and positively correlated to serum TMAO and fecal SCFAs. Conclusions. Our findings uncovered links between intestinal microbiota alterations, circulating endotoxemia, and insulin resistance. This suggests that the underlying mechanism of protection of the intestine by RYGB in obesity may be through changing the gut microbiota.

Dental caries is the most common chronic infectious diseases around the world and disproportionately affects the marginalized socioeconomic group. Streptococcus mutans, considered a primary etiological agent of caries, must depend on the coordinated physiological response to tolerate the oxidative stress generated by commensal species within dental plaque, which is a critical aspect of its pathogenicity. Here, we identified and characterized a novel TetR family regulator SMU_1361c, encoded by the TnSmu2 operon, which appears to be acquired by the bacteria via horizontal genes transfer. Surprisingly, smu_1361c functions as a transcriptional repressor to regulate gene expression outside its operon, involved in the oxidative stress response of S. mutans. The smu_1361c overexpression strain UA159/pDL278-1361c was more susceptible to oxidative stress and less competitive against hydrogen peroxide generated by commensal species Streptococcus gordonii and Streptococcus sanguinis. Transcriptomics analysis revealed that smu_1361c overexpression resulted in the significant downregulation of 22 genes mainly belonging to three gene clusters responsible for the oxidative stress response. The conversed DNA binding motif of SMU_1361c was determined by electrophoretic mobility shift and DNase I footprinting assay with purified SMU_1361c protein, therefore, smu_1361c is directly involved in gene transcription related to the oxidative stress response. Crucially, our finding provides a new understanding of how S. mutans deals with the oxidative stress that is required for pathogenesis and will facilitate the development of new and improved therapeutic approaches for dental caries.

Bone metastases occur in 50–70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 ( EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn’t been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1 , which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182 to enhance its binding to TGFβ receptor type II (TGFβRII), thereby activating TGFβ signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin β1-FAK axis cooperates with the TGFβ signaling pathway to promote bone metastasis of breast cancer. Breast cancer cells are known to metastasize to the bone but why the cells should migrate and metastasize to this particular organ is not clearly understood. Here, the authors show that EZH2 activates an integrin B1 and FAK signaling pathway in breast cancer cells, which activates TGFB signaling to drive metastasis in the bone.

In order to improve the recognition accuracy of graphene pressure sensors, a graphene/silicon pressure sensor array is studied based on backpropagation (BP) neural network. The principle of the pressure sensor array and the workflow of BP neural network are introduced. The 100 groups of training samples ranging from 0 to 1000 kPa are studied based on levenberg‐marquardt (L‐M) optimisation algorithm, and a multiple BP (M‐BP) neural network is designed to improve the recognition accuracy of the pressure sensor array. The training recognition accuracy and test recognition accuracy of M‐BP neural network are about 99.9%. This work plays an important role in the application of graphene pressure sensors in more fields, especially in the solutions for weak pressure detection in artificial intelligence and human‐computer interaction.