Post-translational modification (PTM) refers to the chemical modification of proteins following translation, which influences their structure and function. These modifications can impact protein stability, affinity, activity, and subcellular localization, thereby regulating their biological roles. In the context of oral microbiota, PTMs are integral in modulating protein synthesis, metabolism, and virulence. Oral microorganisms utilize PTMs to adapt to external stimuli and control various physiological processes. To date, over 200 distinct PTMs have been cataloged (Minguez et al., 2012), including both minor chemical modifications (e.g., phosphorylation and acetylation) and the addition of complete proteins (e.g., ubiquitination). The most common PTMs observed in oral microbiota include phosphorylation, acetylation, methylation, glycosylation, sumoylation, and lactylation (Wu et al., 2019; Zeng et al., 2020; Ma et al., 2021b).

Lysine is an amphipathic residue, characterized by a hydrophobic side chain and a positively charged ϵN-group at physiological pH. The ϵN-group in the active or binding site of proteins typically engages in salt bridge formation (Moreira et al., 2007). Acylation of lysine neutralizes the amino group’s positive charge, potentially altering the protein’s conformation. Various acylation modifications have been identified, including acetylation (Wang et al., 2010), malonylation (Peng et al., 2011), crotonylation (Montellier et al., 2012), propionylation and butylation (Chen et al., 2007), and succinylation (Lin et al., 2012). These modifications utilize metabolic intermediates as sensors to regulate metabolism and other processes, thereby coordinating metabolic pathways and signal transduction (Wellen and Thompson, 2012).

The most extensively studied lysine modification is acetylation, which occurs through reversible catalysis by protein acetyltransferases and deacetylases. Active acetyl derivatives, such as acetyl phosphate, acetyl CoA, and acetyladenylic acid, are also known to drive protein acetylation (Ramponi et al., 1975; Wagner and Payne, 2013; Weinert et al., 2013; Kuhn et al., 2014). Initially observed in histones (Allfrey et al., 1964), lysine acetylation has since been identified in various eukaryotic non-histone proteins involved in cellular metabolism, the cell cycle, aging, growth, angiogenesis, and oncogenesis (Chuang et al., 2010; Wang et al., 2010; Zhao et al., 2010; Lu et al., 2011; Carafa et al., 2012; Lin et al., 2012). In contrast, research on prokaryotic acetylation remains limited, primarily focusing on a few microbial species. Although lysine acetylation is increasingly recognized as a significant post-translational modification in bacteria, its specific roles and regulatory mechanisms within oral microbiota remain underexplored.

The oral microenvironment is intricate, shaped by the unique anatomy of the oral cavity. Oral microorganisms are highly sensitive to host factors, including diet, immune status, pH, oral hygiene, oxygen levels, and lifestyle choices (Yan et al., 2023). In contrast to slower regulatory mechanisms such as gene expression and protein turnover, lysine acetylation enables bacteria to rapidly adjust their physiological state, offering a mechanism to respond swiftly to environmental changes. For instance, under hypoxic or anaerobic conditions, lysine acetylation modulates bacterial metabolic pathways, optimizing energy utilization and regulating enzymatic activity to mitigate external stressors (Kim et al., 2015; Martín et al., 2021; Toplak et al., 2022; Ma et al., 2024a).

In addition, protein lysine acetylation is a key regulator of microbial virulence. One noteworthy illustration is the production of extracellular polysaccharides (EPS) by oral bacteria via glucosyltransferases. EPS constitutes the primary component of dental plaque biofilms, promoting bacterial colonization and aggregation. Notably, the acetylation status of glucosyltransferase correlates with its enzymatic activity (Ma et al., 2021a). Beyond local effects, oral pathogens can release virulence factors into the bloodstream, leading to systemic infections. Acetylation plays a critical role in the onset and progression of these virulence factors (Ren et al., 2017).

Protein acetylation differs from mRNA or protein synthesis in that it is not templated, instead depending on the recognition and modification by specific enzymes. This process is typically reversible and dynamic, with chemical groups being added or removed from the polypeptide chain by specialized enzymes. Beyond enzymes, certain chemical compounds also contribute to protein acetylation. For instance, acetyl coenzyme A (Ac-CoA) directly enhances the acetylation of RprY in Porphyromonas gingivalis (Wagner and Payne, 2013). Proteins often undergo multiple modifications, with some residues experiencing several modifications simultaneously. For example, in Porphyromonas gingivalis, acetylation and succinylation frequently overlap, and RprY can concurrently undergo both acetylation and phosphorylation (Li et al., 2018). The interplay between acetylation and other PTMs can produce complementary or antagonistic effects, resulting in intricate combinations that influence the structure and function of target proteins, highlighting the complexity and adaptability of regulatory mechanisms.

Recent advances in enrichment strategies for protein lysine acetylation sites have provided substantial evidence supporting the critical role of protein acetylation in regulating both the physiological and pathological processes of oral microorganisms ( Figure 1 ). This review explores the significance and diverse functions of protein lysine acetylation in oral microorganisms, aiming to fill current knowledge gaps and explore the potential of acetylation as a therapeutic target for oral diseases by integrating emerging evidence across major oral microorganisms, including bacteria (e.g., Streptococcus mutans, Porphyromonas gingivalis) and fungi (e.g., Candida albicans), and highlighting its interplay with other post-translational modifications.

In recent years, the infection rate of Candida albicans, a common opportunistic fungal pathogen, has risen significantly. The growing prevalence of drug resistance and the limited availability of effective antifungal agents present substantial challenges to clinical management. During investigations into its pathogenic mechanisms and drug resistance, lysine acetylation has emerged as a key epigenetic modification. By regulating chromatin structure, gene expression, and signal transduction, lysine acetylation plays a critical role in the growth, virulence, morphological transformation, and stress response of Candida albicans. As such, it represents a promising target for the development of novel antifungal therapies.

Histone acetylation regulates key physiological processes in Candida albicans, such as DNA replication, transcription, and DNA repair, influencing growth, virulence, drug resistance, and environmental adaptability. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) control the acetylation and deacetylation of histones, respectively. During replication, newly synthesized histones are acetylated by HATs, deposited on DNA, and later deacetylated by HDACs; histone chaperones recognize acetylation patterns during this process (Shahbazian and Grunstein, 2007). Additionally, histone acetylation alters chromatin structure, affecting the recruitment of DNA-binding proteins and transcription factors, which in turn modulates gene transcription (Shahbazian and Grunstein, 2007). For example, in Candida albicans, acetylation of H3K56 promotes gene transcriptional activation by increasing chromatin accessibility, with its level closely linked to transcription factor binding on chromatin (Wurtele et al., 2010). This modification creates a favorable environment for gene transcription, reshaping the transcriptional profile of Candida albicans, aiding host adaptation, and enhancing pathogenicity. Rtt109, another HAT, plays a critical role in DNA damage repair and pathogenicity. Deletion of the rtt109 gene results in heightened endogenous DNA damage and increased susceptibility to host macrophages (Lopes da Rosa et al., 2010). Hat1 also contributes significantly to DNA repair; its loss leads to rapid DNA damage accumulation and shifts the growth pattern from yeast to pseudohyphal form, ultimately reducing survival of Candida albicans (Tscherner et al., 2012). These findings emphasize the essential role of histone acetylation in the physiological and pathogenic processes of Candida albicans.

Histone acetylation influences the morphological plasticity of Candida albicans, determining its environmental adaptability and virulence. Candida albicans can transition between yeast, pseudohyphal, and hyphal forms, with the filamentous forms (pseudohyphae and hyphae) playing a critical role in promoting fungal infection and the formation of drug-resistant biofilms (Odds, 1985; Sudbery, 2011). Various enzymes, including HATs and HADCs, are key regulators of this morphological transition. Altered HAT expression significantly impacts Candida albicans’s ability to adapt to environmental changes. For example, deletion of the SWR1 gene, which is involved in H2A.Z histone variant deposition, induces chromatin structure changes, promoting the transition between white and opaque morphologies. The SWR1 complex also regulates nucleosome positioning at the WOR1 promoter, a master regulator of the white-opaque switch essential for maintaining phenotypic plasticity (Guan and Liu, 2015). Additionally, MYST family HATs, such as Esa1 and Sas2, contribute to hyphal growth. Loss of Esa1 specifically impairs hyphal formation without affecting overall growth, highlighting the significance of HATs in regulating morphology and pathogenicity. Moreover, certain HADCs, like the NuA4 complex, regulate histone acetylation via enzymes such as Yng2, further influencing morphological transitions (Wang et al., 2013). These insights emphasize the critical role of histone acetylation in controlling Candida albicans’s morphological plasticity and its adaptation to various host environments and pathogenic states.

Lysine acetylation is integral to Candida albicans’ ability to respond to host immune defenses. This pathogen evades immune detection by modulating the expression of oxidative stress response genes, a process tightly regulated by dynamic histone acetylation (Kim et al., 2018). In addition to transcriptional regulation, acetylation also influences structural adaptations that facilitate immune evasion, as the histone deacetylase Sir2 has been shown to promote systemic candidiasis by remodeling the fungal cell wall, thereby reducing the exposure of immunogenic components like mannan and β-glucan. This remodeling diminishes recognition by the host’s innate immune system and enhances fungal adhesion to host cells, contributing to increased virulence (Yang et al., 2024). Notably, lysine acetylation at specific sites, such as H3K56, influences Candida albicans’s capacity to tolerate oxidative stress and escape immune surveillance (Conte et al., 2024). By altering chromatin structure, histone acetylation modulates gene expression in response to stressors like reactive oxygen species generated by the host immune system. The role of HATs in this process is critical; for instance, Candida albicans deficient in the lysine acetyltransferase Gcn5 exhibits reduced survival in THP-1 macrophages and heightened susceptibility to various stressors (Yu et al., 2022).

Furthermore, interactions between host-derived signals and epigenetic modifications, such as lysine acetylation, influence pathogen morphology, enhancing its adaptability to the host environment. Although the molecular mechanisms underlying these processes remain under investigation, it is evident that lysine acetylation plays a key mediating role in Candida albicans’ resistance to host immune responses.

Lysine acetyltransferases are essential in mediating drug resistance and pathogenicity. The glucosamine-6-phosphate acetyltransferase encoded by the GNA1 gene influences the growth and virulence of Candida albicans, with its deletion resulting in a marked reduction in pathogenicity (Mio et al., 2000). Similarly, the HAT encoded by the NGG1 gene is involved in morphological transformation and virulence; its knockout substantially diminishes the strain’s pathogenic potential (Li et al., 2017a). Furthermore, Hsp90 plays a critical role in drug resistance and morphogenesis. Research has shown that KDACs exhibit functional redundancy in regulating Hsp90 activity, and their inhibition can enhance the effectiveness of antifungal treatments (Li et al., 2017b).

In conclusion, lysine acetylation contributes significantly to the morphological adaptability, immune evasion, and drug resistance of Candida albicans by modulating chromatin structure, gene expression, and stress responses ( Table 4 ). These epigenetic mechanisms not only enhance understanding of Candida albicans pathogenicity but also open avenues for the development of novel antifungal therapies. Although direct evidence of oral-specific acetylation mechanisms is currently lacking, the unique characteristics of the oral environment and the role of acetylation in gene regulation warrant further investigation into this area.

Protein lysine acetylation plays a critical role in microbial physiology, influencing both metabolism and pathogenic potential. Recently, it has garnered significant attention in the context of oral diseases. Lysine acetylation influences the onset and progression of conditions such as dental caries, periodontal disease, and oral mucosal disorders by modulating microbial growth, metabolism, and virulence, offering novel insights and therapeutic strategies for their prevention and treatment.

Histone acetyltransferase-based treatments have been utilized in various clinical applications. Many cellular proteins undergo acetylation post-translationally, resulting in alterations to their structure and function. Consequently, HDAC inhibitors have been developed as therapeutic agents, with two currently approved by the US FDA for the treatment of cutaneous T-cell lymphoma (Richon et al., 2009). Moreover, lysine acetyltransferases are emerging as promising drug targets (Folders et al., 2000).

In dental caries research, aspirin, a non-enzymatic acetylating agent, reduces Gtfs activity in Streptococcus mutans. It also inhibits the growth of Streptococcus mutans and the production of EPS, highlighting the potential of protein acetylation in anti-caries therapies (Lin et al., 2024).

In the gingival tissue of periodontitis patients, dysregulated histone acetylation and deacetylation, along with alterations in DNA methylation, are closely linked to immune and inflammatory responses. In experimental periodontitis models, histone acetylation-targeting treatments, such as HDAC inhibitors (HDACi) or acetylated histone mimetics, effectively prevent alveolar bone loss (Cantley et al., 2011; Meng et al., 2014; Li et al., 2020), offering a novel therapeutic approach for periodontal diseases.

In Candida albicans, lysine 56 of histone H3 undergoes acetylation by the acetyltransferase Rtt109p, and pharmacological inhibition or genetic modulation of this enzyme has been proposed as a potential antifungal therapeutic strategy. Acetylation events, often challenging to detect, can significantly impact protein functions, including stability and crystallinity (Mahon et al., 2015). For therapeutic proteins, such modifications may influence immunogenicity and biological activity, thereby affecting safety and efficacy in clinical applications (Walsh and Jefferis, 2006).

Overall, lysine acetylation plays a key role in regulating the metabolism and pathogenicity of oral pathogens by modulating the activity of critical enzymes. Research in this area not only enhances understanding of the pathogenic mechanisms of oral pathogens but also lays a foundation for the development of novel antibacterial and antifungal therapies. Targeting specific acetylases could substantially improve the efficacy of current treatments and offer potential solutions to manage drug resistance. Future investigations should focus on the role of acetylation in the oral microbiota and its impact on host-pathogen interactions, thus paving the way for new strategies in maintaining oral health and addressing oral diseases.

Acetylation, a key PTM, is central to the functional regulation of oral microorganisms. It modulates various bacterial physiological processes, including metabolism, cell signaling, virulence factor expression, and host-pathogen interactions, by altering protein properties such as structure, activity, localization, and interactions with other biomolecules.

This modification significantly impacts the metabolic state of oral bacteria. While acetylation is typically catalyzed by acetyltransferases, it can also occur non-enzymatically via Ac-CoA (Paik et al., 1970; Yan et al., 2008) or acetyladenylate (Ramponi et al., 1975). As a metabolic intermediate, acetylation enables bacteria to adapt to environmental fluctuations and shifts in metabolic activity, thereby playing a crucial role in the regulation of bacterial physiology and pathogenicity.

Acetylation, along with other PTMs such as succinylation and phosphorylation, collectively regulates bacterial protein functions, forming a complex modification network (Latham and Dent, 2007). This cross-regulation of multiple modifications is essential for controlling bacterial virulence factors, adaptive responses, and metabolic processes. For example, in Porphyromonas gingivalis, substantial overlap has been observed between acetylation and succinylation sites—especially on ribosomal and metabolic proteins—suggesting potential competitive or cooperative regulation of key cellular functions (Zeng et al., 2020). Additionally, the response regulator RprY in Porphyromonas gingivalis is modified by both acetylation and phosphorylation, with each modification exerting distinct effects on its DNA-binding activity and transcriptional regulation (Li et al., 2018). These findings underscore the existence of an intricate PTM crosstalk network that supports bacterial adaptation to fluctuating environmental and host-derived conditions. Nevertheless, systematic studies on the functional interplay among different PTMs in oral microorganisms remain limited. Future research should aim to elucidate the molecular mechanisms and biological consequences of these interactions—particularly the synergistic or antagonistic effects between acetylation, phosphorylation, and succinylation—in governing microbial adaptation, pathogenicity, and immune evasion.

Despite extensive research on acetylation, significant gaps remain in the study of acetylation in oral bacteria. Most investigations have concentrated on a limited number of oral pathogens, such as Porphyromonas gingivalis and Streptococcus mutans. It is important to note that lysine acetylation is a widely conserved modification across diverse oral microbial taxa. Nevertheless, functional studies and comprehensive acetylomic profiling in other clinically relevant oral species—such as Fusobacterium nucleatum, Prevotella intermedia, and Veillonella spp.—remain limited. To address this, future research should broaden the scope of study to include a wider range of oral bacteria and conduct comprehensive acetylomics analyses to better elucidate the acetylation patterns and functions across diverse physiological and pathological states.

From a clinical standpoint, acetylation represents a key mechanism in regulating bacterial virulence and drug resistance, offering potential new targets for the treatment of oral infections. Investigating the role of acetylation in oral microbiota could provide a theoretical foundation for the development of novel antibacterial strategies. Future research should not only examine the fundamental role of acetylation in bacterial function but also explore strategies to mitigate bacterial pathogenicity through acetylation regulation, particularly by targeting the acetylation of key virulence factors to enhance therapeutic outcomes.

In conclusion, acetylation plays a crucial role in the adaptation, virulence, and immune evasion of oral microorganisms. Advances in technologies such as metabolomics, proteomics, and mass spectrometry will further elucidate the role of acetylation in bacterial physiological and pathological processes. This enhanced understanding will not only clarify the mechanisms underlying the virulence of oral bacteria but also open new avenues for the treatment of oral diseases.