lysine acetylation
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2022 ◽  
Vol 27 (1) ◽  
Author(s):  
Hongjuan You ◽  
Qi Li ◽  
Delong Kong ◽  
Xiangye Liu ◽  
Fanyun Kong ◽  
...  

AbstractCanonical Wnt/β-catenin signaling is a complex cell-communication mechanism that has a central role in the progression of various cancers. The cellular factors that participate in the regulation of this signaling are still not fully elucidated. Lysine acetylation is a significant protein modification which facilitates reversible regulation of the target protein function dependent on the activity of lysine acetyltransferases (KATs) and the catalytic function of lysine deacetylases (KDACs). Protein lysine acetylation has been classified into histone acetylation and non-histone protein acetylation. Histone acetylation is a kind of epigenetic modification, and it can modulate the transcription of important biological molecules in Wnt/β-catenin signaling. Additionally, as a type of post-translational modification, non-histone acetylation directly alters the function of the core molecules in Wnt/β-catenin signaling. Conversely, this signaling can regulate the expression and function of target molecules based on histone or non-histone protein acetylation. To date, various inhibitors targeting KATs and KDACs have been discovered, and some of these inhibitors exert their anti-tumor activity via blocking Wnt/β-catenin signaling. Here, we discuss the available evidence in understanding the complicated interaction of protein lysine acetylation with Wnt/β-catenin signaling, and lysine acetylation as a new target for cancer therapy via controlling this signaling.


Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 346
Author(s):  
Meilan Hu ◽  
Fule He ◽  
Erik W. Thompson ◽  
Kostya (Ken) Ostrikov ◽  
Xiaofeng Dai

Acetylation, a reversible epigenetic process, is implicated in many critical cellular regulatory systems including transcriptional regulation, protein structure, activity, stability, and localization. Lysine acetylation is the most prevalent and intensively investigated among the diverse acetylation forms. Owing to the intrinsic connections of acetylation with cell metabolism, acetylation has been associated with metabolic disorders including cancers. Yet, relatively little has been reported on the features of acetylation against the cancer hallmarks, even though this knowledge may help identify appropriate therapeutic strategies or combinatorial modalities for the effective treatment and resolution of malignancies. By examining the available data related to the efficacy of lysine acetylation against tumor cells and elaborating the primary cancer hallmarks and the associated mechanisms to target the specific hallmarks, this review identifies the intrinsic connections between lysine acetylation and cancer hallmarks and proposes novel modalities that can be combined with HDAC inhibitors for cancer treatment with higher efficacy and minimum adverse effects.


2022 ◽  
Author(s):  
Lisa Schuldt ◽  
Katrin von Brandenstein ◽  
Collin Jacobs ◽  
Judit Symmank

The initiation of a spatially and temporally limited inflammation is essential for tissue and bone remodeling by the periodontal ligament (PdL) located between teeth and alveolar bone. Obesity-associated hyperlipidemic changes may impair PdL fibroblast (PdLF) functions, disturbing their inflammatory response to mechanical stress such as those occurring during orthodontic tooth movement (OTM). Recently, we reported an attenuated pro inflammatory response of human PdLF (HPdLF) to compressive forces when stimulated with monounsaturated oleic acid (OA). Fatty acids, including OA, could serve as alternative source of acetyl-CoA, thereby affecting epigenetic histone marks such as histone 3 lysine acetylation (H3Kac) in a lipid metabolism-dependent manner. In this study, we therefore aimed to investigate the extent to which OA exerts its anti-inflammatory effect via changes in H3Kac. Six-hour compressed HPdLF showed increased H3Kac when cultured with OA. Inhibition of histone deacetylases resulted in a comparable IL10 increase as observed in compressed OA cultures. In contrast, inhibition of histone acetyltransferases, particularly p300/CBP, in compressed HPdLF exposed to OA led to an inflammatory response comparable to compressed control cells. OA-dependent increased association of H3Kac to IL10 promoter regions in force-stressed HPdLF further strengthened the assumption that OA exhibits its anti-inflammatory properties via modulation of this epigenetic mark. In conclusion, our study strongly suggests that obesity-related hyperlipidemia affect the functions of PdL cells via alterations in their epigenetic code. Since epigenetic inhibitors are already widely used clinically, they may hold promise for novel approaches to limit obesity-related risks during OTM.


2022 ◽  
Author(s):  
Ting Miao ◽  
Jinoh Kim ◽  
Ping Kang ◽  
Hua Bai

De novo lipogenesis (DNL) is a highly regulated metabolic process, which is known to be activated through transcriptional regulation of lipogenic genes, including fatty acid synthase (FASN). Unexpectedly, we find that the expression of FASN protein remains unchanged during Drosophila larval development when lipogenesis is hyperactive. Instead, acetylation modification of FASN is highly upregulated in fast-growing larvae. We further show that lysine K813 is highly acetylated in developing larvae, and its acetylation is required for upregulated FASN activity, body fat accumulation, and normal development. Intriguingly, K813 is rapidly autoacetylated by acetyl-CoA in a dosage-dependent manner, independent of known acetyltransferases. Furthermore, the autoacetylation of K813 is mediated by a conserved P-loop-like motif (N-xx-G-x-A). In summary, this work uncovers a novel role of acetyl-CoA-mediated autoacetylation of FASN in developmental lipogenesis and reveals a self-regulatory system that controls metabolic homeostasis by linking acetyl-CoA, lysine acetylation, and DNL.


2022 ◽  
Vol 2 (1) ◽  
Author(s):  
Jianfei Guo ◽  
Xiaoqiang Chai ◽  
Yuchao Mei ◽  
Jiamu Du ◽  
Haining Du ◽  
...  

AbstractLysine-ε-acetylation (Kac) is a post-translational modification (PTM) that is critical for metabolic regulation and cell signaling in mammals. However, its prevalence and importance in plants remain to be determined. Employing high-resolution tandem mass spectrometry, we analyzed protein lysine acetylation in five representative Arabidopsis organs with 2 ~ 3 biological replicates per organ. A total of 2887 Kac proteins and 5929 Kac sites were identified. This comprehensive catalog allows us to analyze proteome-wide features of lysine acetylation. We found that Kac proteins tend to be more uniformly expressed in different organs, and the acetylation status exhibits little correlation with the gene expression level, indicating that acetylation is unlikely caused by stochastic processes. Kac preferentially targets evolutionarily conserved proteins and lysine residues, but only a small percentage of Kac proteins are orthologous between rat and Arabidopsis. A large portion of Kac proteins overlap with proteins modified by other PTMs including ubiquitination, SUMOylation and phosphorylation. Although acetylation, ubiquitination and SUMOylation all modify lysine residues, our analyses show that they rarely target the same sites. In addition, we found that “reader” proteins for acetylation and phosphorylation, i.e., bromodomain-containing proteins and GRF (General Regulatory Factor)/14-3-3 proteins, are intensively modified by the two PTMs, suggesting that they are main crosstalk nodes between acetylation and phosphorylation signaling. Analyses of GRF6/14-3-3λ reveal that the Kac level of GRF6 is decreased under alkaline stress, suggesting that acetylation represses plant alkaline response. Indeed, K56ac of GRF6 inhibits its binding to and subsequent activation of the plasma membrane H+-ATPase AHA2, leading to hypersensitivity to alkaline stress. These results provide valuable resources for protein acetylation studies in plants and reveal that protein acetylation suppresses phosphorylation output by acetylating GRF/14-3-3 proteins.


2021 ◽  
Author(s):  
Jie Pei ◽  
Yueming Yuan ◽  
Dayong Tian ◽  
Fei Huang ◽  
Chengguang Zhang ◽  
...  

Rabies, caused by rabies virus (RABV), is a widespread zoonosis that is nearly 100% fatal. Alteration of the metabolic environment affects viral replication and the immune response during viral infection. In this study, glucose uptake was increased in mouse brains at the late stage of infection with different RABV strains (lab-attenuated CVS strain and wild-type DRV strain). To illustrate the mechanism underlying glucose metabolism alteration, comprehensive analysis of lysine acetylation and target analysis of energy metabolites in mouse brains infected with CVS and DRV strains were performed. A total of 156 acetylated sites and 115 acetylated proteins were identified as significantly different during RABV infection. Compared to CVS- and mock-infected mice, the lysine acetylation levels of glycolysis and tricarboxylic acid (TCA) cycle enzymes were decreased, and enzyme activity was upregulated in DRV-infected mouse brains. Metabolomic analysis revealed that high levels of oxaloacetate (OAA) in RABV-infected mouse brains. Specifically, the OAA level in CVS-infected mouse brains was higher than that in DRV-infected mouse brains, which contributed to the enhancement of the metabolic rate at the substrate level. Finally, we confirmed that OAA could reduce excessive neuroinflammation in CVS-infected mouse brains by inhibiting JNK and P38 phosphorylation. Taken together, this study provides fresh insight into the different strategies the host adapts to regulate glucose metabolism for energy requirements after different RABV strain infection and suggest that OAA treatment could be a potential strategy to prevent neural damage during RABV infection. IMPORTANCE Both viral replication and the host immune response are highly energy-dependent. It is important to understand how the rabies virus affects energy metabolism in the brain. Glucose is the direct energy source for cell metabolism. Previous studies have revealed that there is some association between acetylation and metabolic processes. In this study, comprehensive protein acetylation and glucose metabolism analysis were conducted to compare glucose metabolism in mouse brains infected with different RABV strains. Our study demonstrates that the regulation of enzyme activity by acetylation and OAA accumulation at the substrate level are two strategies for the host to respond to the energy requirements after RABV infection. Our study also indicates the potential role OAA could play in neuronal protection by suppressing excessive neuroinflammation.


2021 ◽  
Author(s):  
Zhuochen Lyu ◽  
Shiyuan Luo ◽  
Yinjiao Li ◽  
Liangfang Yao ◽  
Feng Chen ◽  
...  

Abstract Background: Sepsis-associated encephalopathy (SAE) is one of the severe central nervous system complications. Oxidative stress and synaptic dysfunction were involved in cognitive impairment induced by SAE. The mitochondrial nicotinamide adenine dinucleotide (NAD+) dependent deacetylase, sirtuin3 (SIRT3), plays a critical role in regulating mitochondrial function. The aim of this study was to evaluate the effect of SIRT3 in cognitive dysfunction induced by SAE.Methods: Mice were treated with lipopolysaccharide (LPS, 10 mg/kg, i.p.). Contextual and cue memory were evaluated by fear conditioning test in wild-type (WT) and SIRT3-deficient (SIRT3-/-) mice. Synapse-associated proteins and mitochondrial apoptosis-associated protein were examined by western blotting. In vitro studies, acetylation levels of cyclophilin D (CypD) were detected with different SIRT3 deacetylase activity in HT22 cells after LPS-induced microglia supernatant (Mi-sup) exposure. Oxidative stress was detected by reactive oxygen species (ROS) staining, and mitochondrial membrane potential (MMP) was detected by JC-1 staining, and mitochondrial membrane permeability transition pore (MPTP) opening was detected by Calcein and Co2+ staining. Furthermore, the phosphorylation levels of mitochondrial p66Shc and JNK were evaluated by western blotting.Results: SIRT3 expression was diminished in hippocampus of mice after LPS treatment. SIRT3-deficiency contributed to more severe contextual memory loss and synaptic dysfunction, decreased ratio of Bcl-2/Bax and increased Cyt C release to cytoplasm in hippocampus compared with wild-type controls. In HT22 cells, lysine acetylation levels of CypD were significantly increased after Mi-sup exposure and further enhanced with 3-TYP (SIRT3 deacetylation inhibitor) pretreatment, in association with the accumulation of ROS, declined MMP and increased MPTP opening, as well as the increased mitochondrial Cyt C release and phosphorylation levels of mitochondrial JNK and p66Shc-Ser36. SIRT3 overexpression restored CypD lysine acetylation levels and MPTP opening in HT22 cells after Mi-sup exposure and reduced mitochondrial JNK and p66Shc activation. Conclusions: Taken together, our results showed that SIRT3-mediated CypD deacetylation was involved in LPS-induced hippocampal synaptic dysfunction, via ROS accumulation, declined MMP, increased MPTP opening, mitochondrial Cyt C release and mitochondrial apoptosis of hippocampal neuron via JNK/p66Shc pathway. Our results revealed that SIRT3 may be a promising therapeutic and diagnostic target for cognitive dysfunction induced by SAE.


2021 ◽  
Vol 17 (12) ◽  
pp. e1010134
Author(s):  
Qizhao Ma ◽  
Yangyang Pan ◽  
Yang Chen ◽  
Shuxing Yu ◽  
Jun Huang ◽  
...  

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.


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