Coenzyme A (CoA) is an essential cofactor present in all living cells, which plays critical roles in diverse biochemical processes, including cellular metabolism, signal transduction, regulation of gene expression, and the antioxidant response. This review summarizes current knowledge on the role of CoA and its metabolically active thioesters in promoting cellular growth and proliferation (pro-growth) and discusses emerging research on CoA's antioxidant properties that enhance cell survival (pro-survival).

Hippo-YAP signaling is crucial to organ development and tumorigenesis. VGLL4, which occupies TEAD to prevent YAP binding, is the main transcriptional repressor of Hippo-YAP activity. Here we identified the nuclear E3 ligase ubiquitin protein ligase E3 component n-recognin 5 (UBR5) poly-ubiquitinated VGLL4 at Lys61 for its degradation, which permits Hippo-YAP signaling for the development of the liver biliary system in mice and multiple cancers in humans. In mouse liver development, Ubr5 and Vgll4 exhibited reciprocal expression patterns spatiotemporally. Ubr5 deletion impaired cholangiocyte development and hepatocyte reprogramming, which could be efficiently rescued by restoring Hippo-YAP through ablating Vgll4. We also found that the UBR5-VGLL4-YAP axis is associated with the progression of human pan-cancers. Targeting nuclear E3 ligases in multiple types of patient-derived tumor organoids suppressed their expansion. Our identification of UBR5 as the bona fide E3 ligase of VGLL4 offers a molecular framework of nuclear Hippo-YAP regulation and suggests nuclear ubiquitination as a potential therapeutic target for YAP-dependent malignancies.

Aging is a process in which organisms or cells undergo a decline in their functions. Epigenetic modification changes have been recognized as a senescence hallmark in both natural aging and stimulation-induced senescence. An acetylation modification is a dynamic process, which plays a crucial role in the senescence process through DNA stability, metabolism, and signaling pathways. We summarized the role and regulatory pathways of acetylation modifications in senescence. Various cell fate-determining proteins regulate multiple cellular processes through acetylation modifications. These processes interact and coordinate with each other, forming an integrated regulatory network framework that collectively drives cellular senescence via multiple systemic mechanisms. Based on these findings, we proposed the "acetylation-network regulation-cellular senescence" model, to elaborate how acetylation contributes to senescence. We believe this insight could provide new directions and intervention strategies for senescence and aging-related diseases.

Over the years, caloric intake has remained a subject of profound scrutiny. Within the scientific community, there has been rigorous debate to ascertain which path is most ideal for enhancing quality of life and extending the human lifespan. Caloric restriction has been shown to be a promising contributor towards longevity and delaying the onset of age-related diseases. This diet consists of a reduction in caloric intake while maintaining essential energy and nutritional requirements to achieve optimal health while avoiding malnutrition. However, the effects of this nutritional regimen on male reproductive health have not yet been comprehensively studied. Nevertheless, such a complex process will certainly be regulated by a variety of metabolic sensors, likely sirtuins. Evidence has been gathered regarding this group of enzymes, and their ability to regulate processes such as chromatin condensation, the cell cycle, insulin signaling, and glucose and lipid metabolism, among many others. Concerning testicular function and male fertility, sirtuins can modulate certain metabolic processes through their interaction with the hypothalamic-pituitary-gonadal axis and mitochondrial dynamics, among many others, which remain largely unexplored. This review explores the impact of caloric restriction on male fertility, highlighting the emerging role of sirtuins as key regulators of male reproductive health through their influence on cellular metabolism.

Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.

Microcalcification increases the vulnerability of plaques and has become an important driver of acute cardiovascular events in diabetic patients. However, the regulatory mechanisms remain unclear. DJ-1, a multifunctional protein, may play a potential role in the development of diabetic complications. Therefore, this study aims to explore the relationship between DJ-1 and microcalcification in diabetic plaques and investigate the mechanisms.

The regulatory relationship between DJ-1 and diabetic vascular microcalcification was determined in anterior tibial arteries from diabetic foot amputated patients, a diabetic apolipoprotein E-deficient (ApoE-/-) mouse model, and a vascular smooth muscle cell (VSMC) model. The ubiquitination and acetylation levels of DJ-1 were detected, and the acetylation-ubiquitination crosstalk was explored. Then, the regulatory effects of DJ-1 on receptor for advanced glycation end products (RAGE) were clarified. Further, the role of DJ-1 in collagen-matrix vesicles (MVs) interaction in diabetic microenvironment was observed. The collagen interacting surface protein of MVs was verified with proteomics and the biomimetic MVs model. In clinical samples, the number of microcalcification nodules in anterior tibial artery plaques was negatively correlated with DJ-1 expression. In diabetic ApoE-/- mice and VSMCs models, knocking down DJ-1 significantly increased the number of microcalcified nodules. N-acetyltransferase 10 (NAT10) was an acetyltransferase of DJ-1. NAT10 could crosstalk the ubiquitination of DJ-1 and enhance the ubiquitination of DJ-1 by E3 ubiquitin ligase tripartite motif-containing protein 32 (TRIM32). Besides, the knockdown of DJ-1 activated signal transducer and activator of transcription 1 (STAT1), and then STAT1 could bind to RAGE promoter, thus up-regulating RAGE. Furthermore, the knockdown of DJ-1 significantly promoted collagen-MVs interaction in diabetic microenvironment. Milk fat globule epidermal growth factor 8 (MFGE8) may serve as a collagen-interacting protein. The coating of MFGE8 protein could increase the interaction between collagen and biomimetic MVs.

In the diabetic microenvironment, DJ-1 was a protective factor for vascular microcalcification. NAT10- and TRIM32-mediated acetylation-ubiquitination crosstalk resulted in the degradation of DJ-1. The decrease of DJ-1 could activate DJ-1/STAT1/RAGE microcalcification signal. Further, under the stimulation of DJ-1-mediated microcalcification signal, VSMCs released MVs with high abundance of MFGE8. MFGE8 promoted collagen-MVs interaction and finally accelerated the formation of microcalcification.

Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system and accounts for more than 90 % of all renal tumors. Resistance to targeted therapy has emerged as a pivotal factor that contributes to the progressive deterioration of patients with advanced RCC. Metabolic reprogramming is a hallmark of tumorigenesis and progression, with an increasing body of evidence indicating that abnormal lipid metabolism plays a crucial role in the advancement of renal clear cell carcinoma.

Clarify the precise mechanisms underlying abnormal lipid metabolism and drug resistance.

Bioinformatics screening and analyses were performed to identify hub gene. qRT-PCR, western blot, chromatin immunoprecipitation (ChIP) assays, and other biological methods were used to explore and verify related pathways. Various cell line models and animal models were used to perform biological functional experiments.

In this study, we identified Mesoderm induction early response 2 (MIER2) as a novel biomarker for RCC, demonstrating its role in promoting malignancy and sunitinib resistance by influencing lipid metabolism in RCC. Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. Furthermore, Trichostatin A (TSA), an inhibitor of HDAC1, was found to impede the MIER2/HDAC1/P53/PGC1A pathway, offering potential benefits for patients with sunitinib-resistant renal cell cancer.

Our findings highlight MIER2 as a key player in anchoring HDAC1 and inhibiting PGC1A expression through the deacetylation of P53, thereby inducing lipid accumulation in RCC and promoting drug resistance. Lipid-rich RCC cells compensate for energy production and sustain their own growth in a glycolysis-independent manner, evading the cytotoxic effects of targeted drugs and ultimately culminating in the development of drug resistance.

Mitochondria are key organelles that perform and coordinate various metabolic processes in the cell, and their homeostasis is essential for the maintenance of eukaryotic life. To maintain mitochondrial homeostasis and cellular health, close communication between noncoding RNAs (ncRNAs) and proteins is required. For example, there are numerous crosstalk between ncRNAs and the sirtuin (SIRT1-7) family, which is a group of nicotinamide adenine dinucleotides (NAD(+))-dependent Type III deacetylases. NcRNAs are involved in the regulation of gene expression of sirtuin family members, and deacetylation of sirtuin family members can also influence the generation of ncRNAs. This review focuses on the relationship between the two mentioned above and summarizes the impact of their interactions on mitochondrial metabolism, oxidative stress, mitochondrial apoptotic pathways, mitochondrial biogenesis, mitochondrial dynamics, and other mitochondria-related pathophysiological processes. Finally, the review also describes targeted and appropriate treatment strategies. In conclusion, we provide an overview of the ncRNA-sirtuins/mitochondria relationship that could provide a reference for related research in the mitochondrial field and help the future development of new biomedical applications in this area.

SIRT2 (sirtuin2) is a NAD+-dependent deacetylase implicated in fibrosis and inflammation of the liver, kidney, and heart. In this study, we designed and synthesized a series of 3-naphthylthiophene derivatives and evaluated their inhibitory activity against the SIRT2 enzyme. Among them, Z18 demonstrated outstanding SIRT2 inhibitory activity and selectivity. It significantly inhibited both the proliferation of cardiac fibroblasts (CFs) and the activity and expression of SIRT2 in CFs. Moreover, compound Z18 effectively suppressed TGF-β1-induced increases in α-SMA and CoL-1A1 protein expression, as well as hydroxyproline levels. Pharmacological mechanism tests demonstrated that Z18 inhibited SIRT2, thereby suppressing the TGF-β1-induced autocrine production of TGF-β1 and the phosphorylation of Smad2/3 in CFs. In MTT assays, Z18 exhibited a significant inhibitory effect on the proliferation of CFs induced by TGF-β1. In vivo, Z18 effectively ameliorated TAC- and ISO-induced declines in cardiac function, histopathological morphological changes, and collagen deposition. It also inhibited SIRT2 activity and reduced the expression of α-SMA and p-Smad2/3. In hepatorenal toxicity assays, Z18 exhibited an excellent safety profile. These results support the further development of the selective SIRT2 inhibitor Z18 as a potential lead compound for the treatment of myocardial fibrosis.

Excessive oxidative stress is known to cause endothelial dysfunction and drive cardiovascular diseases (CVD). While telomerase reverse transcriptase (TERT) shows protective effects against oxidative stress in rodents and is associated to human flow-mediated dilation in CVD, its regulatory mechanisms in human vascular systems under pathological oxidative stress require further investigation.

Human induced pluripotent stem cells (hiPSCs) were used to create vascular organoids (VOs). These VOs and human umbilical vein endothelial cells (HUVECs) were subjected to oxidative stress through both hydrogen peroxide (H2O2) and oxidized low-density lipoprotein (oxLDL) models. The effects of TERT overexpression by inhibition of the ubiquitin protein ligase E3 component N-recognin 5 (UBR5) on reactive oxygen species (ROS)-induced vascular injury and cellular senescence were assessed using neovascular sprouting assays, senescence-associated β-galactosidase (SA-β-Gal) staining, and senescence-associated secretory phenotype (SASP) assays.

ROS significantly impaired VO development and endothelial progenitor cell (EPC) angiogenesis, evidenced by reduced neovascular sprouting and increased senescence markers, including elevated SA-β-Gal activity and SASP-related cytokine levels. Overexpression of TERT counteracted these effects, restoring VO development and EPC function. Immunoprecipitation-mass spectrometry identified UBR5 as a critical TERT regulator, facilitating its degradation. Inhibition of UBR5 stabilized TERT, improving VO angiogenic capacity, and reducing SA-β-Gal activity and SASP cytokine levels.

Inhibiting UBR5 stabilizes TERT, which preserves EPC angiogenic capacity, reduces VO impairment, and delays endothelial cell senescence under oxidative stress. These findings highlight the potential of targeting UBR5 to enhance vascular health in oxidative stress-related conditions.

Recently, changes in metabolites and metabolism-related enzymes related to tumor cell proliferation, metastasis, drug resistance, and immunosuppression have become a research hotspot, and researchers have attempted to determine the clinical correlation between specific molecular lesions and metabolic phenotypes. Convincing evidence shows that metabolic reprogramming is closely related to the proliferation, invasion, metastasis, and poor prognosis of malignant tumors. Therefore, targeting metabolic reprogramming is a new direction for cancer treatment. However, how molecular alterations in tumors contribute to metabolic diversity and unique targeting dependencies remains unclear. A full understanding of the underlying mechanisms of metabolic reprogramming in cancer may lead to better identification of therapeutic targets and the development of therapeutic strategies. Evidence for the importance of PCK1, a phosphoenolpyruvate carboxykinase 1, in tumorigenesis and development is accumulating. PCK1 can regulate cell proliferation and metastasis by remodeling cell metabolism. Additionally, PCK1 has "nonclassical" nonmetabolic functions, involving the regulation of gene expression, angiogenesis, epigenetic modification, and other processes, and has an impact on cell survival, apoptosis, and other biological activities, as well as the remodeling of the tumor immune microenvironment. Herein, we provide a comprehensive overview of the functions of PCK1 under physiological and pathological conditions and suggest that PCK1 is a potential target for cancer therapy. We also propose a future exploration direction for targeting PCK1 for cancer therapy from a clinical perspective. Finally, in view of the collective data, the results of our discussion suggest the potential clinical application of targeted PCK1 therapy in combination with chemotherapy and immunotherapy for cancer treatment.

Circular RNAs (circRNAs) are a type of regulatory RNA that feature covalently closed single-stranded loops. Evidence suggested that circRNAs play important roles in the progression and development of various cancers. However, the impact of circRNA on autophagy-mediated progression of colorectal cancer (CRC) remains unclear. The objective of this project was to investigate the influence of circSEC24B on autophagy and its underlying mechanisms in CRC. To validate the presence and circular structure of circSEC24B in CRC cells and tissues, PCR and Sanger sequencing techniques were employed. Drug resistance and invasive phenotype of CRC cells were evaluated using CCK8, transwell, and Edu assays. Gain- and loss-of-function experiments were conducted to assess the effects of circSEC24B and its protein partner on the growth, invasion, and metastasis of CRC cells in vitro and in vivo. Interactions between circSEC24B, OTUB1, and SRPX2 were analyzed through immunofluorescence, RNA-pulldown, and RIP assays. Mass spectrometry analysis was used to identify potential binding proteins of circRNA in CRC cells. Vectors were constructed to investigate the specific structural domain of the deubiquitinating enzyme OTUB1 that binds to circSEC24B. Results showed that circSEC24B expression was increased in CRC tissues and cell lines, and it enhanced CRC cell proliferation and autophagy levels. Mechanistically, circSEC24B promoted CRC cell proliferation by regulating the protein stability of SRPX2. Specifically, circSEC24B acted as a scaffold, facilitating the binding of OTUB1 to SRPX2 and thereby enhancing its protein stability. Additionally, evidence suggested that OTUB1 regulated SRPX2 expression through an acetylation-dependent mechanism. In conclusion, this study demonstrated that circSEC24B activated autophagy and induced chemoresistance in CRC by promoting the deubiquitination of SRPX2, mediated by the deubiquitinating enzyme OTUB1.

Understanding molecular mechanisms of plant cellular response to heat stress will help to improve crop tolerance and yield in the global warming era. Here, we show that deacetylation of non-histone proteins mediated by cytoplasmic histone deacetylase HDA714 is required for plant tolerance to heat stress in rice. Heat stress reduces overall protein lysine acetylation, which depends on HDA714. Being induced by heat stress, HDA714 loss of function reduces, but its overexpression enhances rice tolerance to heat stress. Under heat stress, HDA714-mediated deacetylation of metabolic enzymes stimulates glycolysis. In addition, HDA714 protein is found within heat-induced stress granules (SGs), and many SG proteins are acetylated under normal temperature. HDA714 interacts with and deacetylates several SG proteins. HDA714 loss of function increases SG protein acetylation levels and impairs SG formation. Collectively, these results indicate that HDA714 responds to heat stress to deacetylate cellular proteins, control metabolic activities, stimulate SG formation, and confer heat tolerance in rice.

Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2-/- males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise compared to wild type controls. Conversion of injected lactate, pyruvate, and glycerol boluses into glucose via gluconeogenesis was impaired, but only in males. Primary Sirt2-/- male hepatocytes exhibited reduced glycolysis and reduced mitochondrial respiration. RNAseq and proteomics were used to interrogate the mechanisms behind this liver phenotype. Loss of Sirt2 did not lead to transcriptional dysregulation, as very few genes were altered in the transcriptome. In keeping with this, there were also negligible changes to protein abundance. Site-specific quantification of the hepatic acetylome, however, showed that 13% of all detected acetylated peptides were significantly increased in Sirt2-/- male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2-/- female liver. The target sites in the male liver were distributed across mitochondria (44%), cytoplasm (32%), nucleus (8%), and other compartments (16%). Despite the high number of putative mitochondrial Sirt2 targets, Sirt2 antigen was not detected in purified wild type liver mitochondria, suggesting that Sirt2's regulation of mitochondrial function occurs from outside the organelle. We conclude that Sirt2 regulates hepatic protein acetylation and metabolism in a sex-specific manner.

The circadian clock is the inner rhythm of life activities and is controlled by a self-sustained and endogenous molecular clock, which maintains a ~ 24 h internal oscillation. As the core element of the circadian clock, BMAL1 is susceptible to degradation through the ubiquitin-proteasome system (UPS). Nevertheless, scant information is available regarding the UPS enzymes that intricately modulate both the stability and transcriptional activity of BMAL1, affecting the cellular circadian rhythm. In this work, we identify and validate UBR5 as a new E3 ubiquitin ligase that interacts with BMAL1 by using affinity purification, mass spectrometry, and biochemical experiments. UBR5 overexpression induced BMAL1 ubiquitination, leading to diminished stability and reduced protein level of BMAL1, thereby attenuating its transcriptional activity. Consistent with this, UBR5 knockdown increases the BMAL1 protein. Domain mapping discloses that the C-terminus of BMAL1 interacts with the N-terminal domains of UBR5. Similarly, cell-line-based experiments discover that HYD, the UBR5 homolog in Drosophila, could interact with and downregulate CYCLE, the BMAL1 homolog in Drosophila. PER2-luciferase bioluminescence real-time reporting assay in a mammalian cell line and behavioral experiments in Drosophila reveal that UBR5 or hyd knockdown significantly reduces the period of the circadian clock. Therefore, our work discovers a new ubiquitin ligase UBR5 that regulates BMAL1 stability and circadian rhythm and elucidates the underlying molecular mechanism. This work provides an additional layer of complexity to the regulatory network of the circadian clock at the post-translational modification level, offering potential insights into the modulation of the dysregulated circadian rhythm.

Ubiquitinases are known to catalyze ubiquitin chains on target proteins to regulate various physiological functions like cell proliferation, autophagy, apoptosis, and cell cycle progression. As a member of E3 ligase, ubiquitin protein ligase E3 component n-recognin 5 (UBR5) belongs to the HECT E3 ligase and has been reported to be correlated with various pathophysiological processes. In this review, the authors give a comprehensive insight into the structure and function of UBR5. The authors discuss the specific domains of UBR5 and explore their biological functions separately. Furthermore, the authors describe the involvement of UBR5 in different pathophysiological conditions, including immune response, virus infection, DNA damage response, and protein quality control. Moreover, the authors provide a thorough summary of the important roles and regulatory mechanisms of UBR5 in cancers and other diseases. On the whole, investigating the domains and functions of UBR5, elucidating the underlying mechanisms of UBR5 with various substrates in detail may provide new theoretical basis for the treatment of diseases, including cancers, which could improve future studies to construct novel UBR5-targeted therapy strategies.

To assess and validate the gene expression profile of SIRTs (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7) in relation to the pathogenesis and prognostic progression of Myelodysplastic neoplasm (MDS). Eighty bone marrow samples of patients with de novo MDS were diagnosed according to WHO 2022 and IPSS-R criteria. Ten bone marrow samples were obtained from elderly healthy volunteers and used as control samples. Gene expression levels of all SIRTs were assessed using RT-qPCR assays. Downregulation of SIRT2 (p = 0.009), SIRT3 (p = 0.048), SIRT4 (p = 0.049), SIRT5 (p = 0.046), SIRT6 (p = 0.043), and SIRT7 (p = 0.047) was identified in MDS patients compared to control individuals. Also, we identified that while SIRT2-7 genes are typically down-regulated in MDS patients compared to normal controls, there are relative expression variations among MDS patient subgroups. Specifically, SIRT4 (p = 0.029) showed increased expression in patients aged 60 or above, and both SIRT2 (p = 0.016) and SIRT3 (p = 0.036) were upregulated in patients with hemoglobin levels below 8 g/dL. SIRT2 (p = 0.045) and SIRT3 (p = 0.033) were highly expressed in patients with chromosomal abnormalities. Different SIRTs exhibited altered expression patterns concerning specific MDS clinical and prognostic characteristics. The downregulation in SIRTs genes (e.g., SIRT2 to SIRT7) expression in Brazilian MDS patients highlights their role in the disease's development. The upregulation of SIRT2 and SIRT3 in severe anemia patients suggests a potential link to manage iron overload-related complications in transfusion-dependent patients. Moreover, the association of SIRT2/SIRT3 with genomic instability and their role in MDS progression signify promising areas for future research and therapeutic targets. These findings underscore the importance of SIRT family in understanding and addressing MDS, offering novel clinical, prognostic, and therapeutic insights for patients with this condition.

The NAD+-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from Schistosoma mansoni (SmSirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the "Kinetobox" library as a dual inhibitor of human Sirt2 (hSirt2) and SmSirt2. Herein, we describe the structure-activity studies on 1,2,4-oxadiazole-based analogues, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate-competitive and cofactor-noncompetitive binding mode of inhibition could be determined in vitro via binding assays and kinetic analysis and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogues reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.

Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.

PRMT1 plays many important roles in both normal and disease biology, thus understanding it's regulation is crucial. Herein, we report the role of p300-mediated acetylation at K228 in triggering PRMT1 degradation through FBXL17-mediated ubiquitination. Utilizing mass-spectrometry, cellular biochemistry, and genetic code-expansion technologies, we elucidate a crucial mechanism independent of PRMT1 transcript levels. These results underscore the significance of acetylation in governing protein stability and expand our understanding of PRMT1 homeostasis. By detailing the molecular interplay between acetylation and ubiquitination involved in PRMT1 degradation, this work contributes to broader efforts in deciphering post-translational mechanisms that influence protein homeostasis.

Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.

Sirtuins (SIRTs) represent a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that exert a crucial role in cellular signal transduction and various biological processes. The mammalian sirtuins family encompasses SIRT1 to SIRT7, exhibiting therapeutic potential in counteracting cellular aging, modulating metabolism, responding to oxidative stress, inhibiting tumors, and improving cellular microenvironment. These enzymes are intricately linked to the occurrence and treatment of diverse pathological conditions, including cancer, autoimmune diseases, and cardiovascular disorders. Given the significance of histone modification in gene expression and chromatin structure, maintaining the equilibrium of the sirtuins family is imperative for disease prevention and health restoration. Mounting evidence suggests that modulators of SIRTs play a crucial role in treating various diseases and maintaining physiological balance. This review delves into the molecular structure and regulatory functions of the sirtuins family, reviews the classification and historical evolution of SIRTs modulators, offers a systematic overview of existing SIRTs modulation strategies, and elucidates the regulatory mechanisms of SIRTs modulators (agonists and inhibitors) and their clinical applications. The article concludes by summarizing the challenges encountered in SIRTs modulator research and offering insights into future research directions.

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

LC3 lipidation plays an important role in the regulation of macroautophagy and LC3-associated microautophagy. The E1-like enzyme ATG7 is one of the core components that are directly involved in LC3 lipidation reaction. Here, we provide evidence showing that acetylation of ATG7 tightly controls its enzyme activity to regulate the induction of macroautophagy and LC3-associated microautophagy. Mechanistically, acetylation of ATG7 disrupts its interaction with the E2-like enzyme ATG3, leading to an inhibition of LC3 lipidation in vitro and in vivo. Functionally, in response to various different stimuli, cellular ATG7 undergoes deacetylation to induce macroautophagy and LC3-associated microautophagy, which are necessary for cells to eliminate cytoplasmic DNA and degrade lysosome membrane proteins, respectively. Taken together, these findings reveal that ATG7 acetylation acts as a critical rheostat in controlling LC3 lipidation and related cellular processes.Abbreviations: AMPK: AMP-activated protein kinase; ATG: autophagy-related; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; CREBBP/CBP: CREB binding protein; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EP300/p300: E1A binding protein p300; IFNB1: interferon beta 1; ISD: interferon stimulatory DNA; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAM: nicotinamide; PE: phosphatidylethanolamine; PTM: post-translational modification; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SIRT: sirtuin; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TSA: trichostatin A; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2; WT: wild-type.

The decline in female fecundity is linked to advancing chronological age. The ovarian reserve diminishes in quantity and quality as women age, impacting reproductive efficiency and the aging process in the rest of the body. NAD+ is an essential coenzyme in cellular energy production, metabolism, cell signaling, and survival. It is involved in aging and is linked to various age-related conditions. Hallmarks associated with aging, diseases, and metabolic dysfunctions can significantly affect fertility by disturbing the delicate relationship between energy metabolism and female reproduction. Enzymes such as sirtuins, PARPs, and CD38 play essential roles in NAD+ biology, which actively consume NAD+ in their enzymatic activities. In recent years, NAD+ has gained much attention for its role in aging and age-related diseases like cancer, Alzheimer's, cardiovascular diseases, and neurodegenerative disorders, highlighting its involvement in various pathophysiological processes. However, its impact on female reproduction is not well understood. This review aims to bridge this knowledge gap by comprehensively exploring the complex interplay between NAD+ biology and female reproductive aging and providing valuable information that could help develop plans to improve women's reproductive health and prevent fertility issues.

Mammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, Cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rb's concentration decreases during G1 to promote cells progressing through the G1/S transition. However, the mechanisms underlying this second pathway are unknown. Here, we found that Rb's concentration drop in G1 and recovery in S/G2 is controlled by phosphorylation-dependent protein degradation. In early G1 phase, un- and hypo-phosphorylated Rb is targeted by the E3 ligase UBR5. UBR5 knockout cells have higher Rb concentrations in early G1, exhibit a lower G1/S transition rate, and are more sensitive to Cdk4/6 inhibition. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 (MKRN1) and promoting the expression of the dominant and oncogenic isoform, MKRN1-T1. Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.

It is well known that preslaughter (antemortem) stress such as rough handling, transportation, a negative environment, physical discomfort, lack of consistent routine, and bad feed quality has a big impact on meat quality. The antemortem-induced poor meat quality is characterized by low pH, a pale and exudative appearance, and a soft texture. Previous studies indicate that antemortem stress plays a key role in regulating protein acetylation and glycolysis in postmortem (PM) muscle. However, the underlying molecular and biochemical mechanism is not clearly understood yet. In this study, we investigated the relationship between antemortem and protein acetylation and glycolysis using murine longissimus dorsi muscle isolated from ICR mice and murine muscle cell line C2C12 treated with epinephrine hydrochloride. Because adrenaline secretion increases in stressed animals, epinephrine hydrochloride was intraperitoneally injected epinephrine into mice to simulate pre-slaughter stress in this study to facilitate experimental operations and save experimental costs. Our findings demonstrated that protein acetylation in pyruvate kinase M1 (PKM1) form is significantly reduced by antemortem, and the reduced acetylation subsequently leads to an increase in PKM1 enzymatic activity which causes increased glycolysis in PM muscle. By using molecular approaches, we identified lysine 141 in PKM1 as a critical residue for acetylation. Our results in this study provide useful insight for controlling or improving meat quality in the future.

In many neurodegenerative disorders, such as Alzheimer's disease (AD), glutamate-mediated neuronal excitotoxicity is considered the basis for cognitive impairment. The mRNA and protein expression of SERPINA4(Kallistatin) are higher in patients with AD. However, whether Kallistatin plays a regulatory role in glutamate-glutamine cycle homeostasis remains unclear. In this study, we identified impaired cognitive function in Kallistatin transgenic (KAL-TG) mice. Baseline glutamate levels were elevated and miniature excitatory postsynaptic current (mEPSC) frequency was increased in the hippocampus, suggesting the impairment of glutamate homeostasis in KAL-TG mice. Mechanistically, we demonstrated that Kallistatin promoted lysine acetylation and ubiquitination of glutamine synthetase (GS) and facilitated its degradation via the proteasome pathway, thereby downregulating GS. Fenofibrate improved cognitive memory in KAL-TG mice by downregulating serum Kallistatin. Collectively, our study findings provide insights the mechanism by which Kallistatin regulates cognitive impairment, and suggest the potential of fenofibrate to prevente and treat of AD patients with high levels of Kallistatin.

Mesenchymal stem cells (MSCs) are stem/progenitor cells capable of self-renewal and differentiation into osteoblasts, chondrocytes and adipocytes. The transformation of multipotent MSCs to adipocytes mainly involves two subsequent steps from MSCs to preadipocytes and further preadipocytes into adipocytes, in which the process MSCs are precisely controlled to commit to the adipogenic lineage and then mature into adipocytes. Previous studies have shown that the master transcription factors C/enhancer-binding protein alpha and peroxisome proliferation activator receptor gamma play vital roles in adipogenesis. However, the mechanism underlying the adipogenic differentiation of MSCs is not fully understood. Here, the current knowledge of adipogenic differentiation in MSCs is reviewed, focusing on signaling pathways, noncoding RNAs and epigenetic effects on DNA methylation and acetylation during MSC differentiation. Finally, the relationship between maladipogenic differentiation and diseases is briefly discussed. We hope that this review can broaden and deepen our understanding of how MSCs turn into adipocytes.

Histone acetylation is a predominant active chromatin mark deposited by histone acetyltransferases (HATs) that transfer the acetyl group from acetyl coenzyme A (acetyl-CoA) to lysine ε-amino groups in histones. GENERAL CONTROL NON-REPRESSED PROTEIN 5 (GCN5) is one of the best-characterized HATs and functions in association with several adaptor proteins such as ADA2 within multiprotein HAT complexes. ADA2-GCN5 interaction increases GCN5 binding to acetyl-CoA and stimulates its HAT activity. It remains unclear whether the HAT activity of GCN5 (which acetylates not only histones but also cellular proteins) is regulated by acetyl-CoA levels, which vary greatly in cells under different metabolic and nutrition conditions. Here we show that the ADA2 protein itself is acetylated by GCN5 in rice cells. Lysine acetylation exposes ADA2 to a specific E3 ubiquitin ligase and reduces its protein stability. In rice plants, ADA2 protein accumulation reversely parallels its lysine acetylation and acetyl-CoA levels, both of which are dynamically regulated under varying growth conditions. Stress-induced ADA2 accumulation could stimulate GCN5 HAT activity to compensate for the reduced acetyl-CoA levels for histone acetylation. These results indicate that ADA2 lysine acetylation that senses cellular acetyl-CoA variations is a mechanism to regulate HAT activity and histone acetylation homeostasis in plants under changing environments.

Liver disease has become one of the main causes of health issue worldwide. Sirtuin (Sirt) 2 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, and is expressed in multiple organs including liver, which plays important and complex roles by interacting with various substrates. Physiologically, Sirt2 can improve metabolic homeostasis. Pathologically, Sirt2 can alleviate inflammation, endoplasmic reticulum (ER) stress, promote liver regeneration, maintain iron homeostasis, aggravate fibrogenesis and regulate oxidative stress in liver. In liver diseases, Sirt2 can mitigate fatty liver disease (FLD) including non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD), but aggravate hepatitis B (HBV) and liver ischemia-reperfusion injury (LIRI). The role of Sirt2 in liver cancer and aging-related liver diseases, however, has not been fully elucidated. In this review, these biological processes regulated by Sirt2 in liver are summarized, which aims to update the function of Sirt2 in liver and to explore the potential role of Sirt2 as a therapeutic target for liver diseases.

Gasdermin D (GSDMD) functions as a pivotal executor of pyroptosis, eliciting cytokine secretion following cleavage by inflammatory caspases. However, the role of posttranslational modifications (PTMs) in GSDMD-mediated pyroptosis remains largely unexplored. In this study, we demonstrate that GSDMD can undergo acetylation at the Lysine 248 residue, and this acetylation enhances pyroptosis. We identify histone deacetylase 4 (HDAC4) as the specific deacetylase responsible for mediating GSDMD deacetylation, leading to the inhibition of pyroptosis both in vitro and in vivo. Deacetylation of GSDMD impairs its ubiquitination, resulting in the inhibition of pyroptosis. Intriguingly, phosphorylation of HDAC4 emerges as a critical regulatory mechanism promoting its ability to deacetylate GSDMD and suppress GSDMD-mediated pyroptosis. Additionally, we implicate Protein phosphatase 1 (PP1) catalytic subunits (PP1α and PP1γ) in the dephosphorylation of HDAC4, thereby nullifying its deacetylase activity on GSDMD. This study reveals a complex regulatory network involving HDAC4, PP1, and GSDMD. These findings provide valuable insights into the interplay among acetylation, ubiquitination, and phosphorylation in the regulation of pyroptosis, offering potential targets for further investigation in the field of inflammatory cell death.

Although myeloid-derived suppressor cells (MDSCs) are critical for allograft survival, their regulatory mechanism remains unclear. Herein, our results showed that metabolism sensor sirtuin 2 (SIRT2) negatively regulates the functions of MDSCs in inducing allogeneic skin graft rejection. Genetic deletion of SIRT2 in myeloid cells (Sirt2Δmye) increased the number of CD11b+Gr1+ MDSCs in bone marrow, spleens, draining lymph nodes, and allografts, inhibited the production of proinflammatory cytokine tumor necrosis factor ɑ, enhanced the production of anti-inflammatory cytokine interleukin 10, and potentiated the suppressive activation of MDSCs in prolonging allograft skin survival. C-X-C motif chemokine receptor 2 is critical for mediating the recruitment and cytokine production of MDSCs induced by SIRT2. Mechanistically, Sirt2Δmye enhanced NAD+ levels, succinate dehydrogenase subunit A (SDHA) activities, and oxidative phosphorylation (OXPHOS) levels in MDSCs after transplantation. Pharmacologically blocking nicotinamide phosphoribosyltransferase effectively reverses the production of cytokines and suppressive activities of MDSC induced by Sirt2Δmye. Blocking OXPHOS with knockdown of SDHA or pharmacological blocking of SDHA significantly restores Sirt2Δmye-mediated stronger MDSC suppressive activity and inflammatory factor productions. Thus, our findings identify a previously unrecognized interplay between NAD+ and SDH-mediated OXPHOS metabolic pathways in regulating MDSC functions induced by the metabolic sensor SIRT2 in allogeneic transplantation.

Glioblastoma (GBM) is a primary tumor in the intracranial compartment. Vasculogenic mimicry (VM) is a process in which a pipeline of tumor cells that provide blood support to carcinogenic cells is formed, and studying VM could provide a new strategy for clinical targeted treatment of GBM. In the present study, we found that SNORD17 and ZNF384 were significantly upregulated and promoted VM in GBM, whereas KAT6B was downregulated and inhibited VM in GBM. RTL-P assays were performed to verify the 2'-O-methylation of KAT6B by SNORD17; IP assays were used to detect the acetylation of ZNF384 by KAT6B. In addition, the binding of ZNF384 to the promoter regions of VEGFR2 and VE-cadherin promoted transcription, as validated by chromatin immunoprecipitation and luciferase reporter assays. And finally, knockdown of SNORD17 and ZNF384 combined with KAT6B overexpression effectively reduced the xenograft tumor size, prolonged the survival time of nude mice and reduced the number of VM channels. This study reveals a novel mechanism of the SNORD17/KAT6B/ZNF384 axis in modulating VM development in GBM that may provide a new goal for the comprehensive treatment of GBM.