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Cellular metabolites, such as acyl-CoA, can modify proteins, leading to protein posttranslational modifications (PTMs). One such PTM is lysine succinylation, which is regulated by sirtuin 5 (SIRT5). Although numerous proteins are modified by lysine succinylation, the physiological significance of lysine succinylation and SIRT5 remains elusive. Here, by profiling acyl-CoA molecules in various mouse tissues, we have discovered that different tissues have different acyl-CoA profiles and that succinyl-CoA is the most abundant acyl-CoA molecule in the heart. This interesting observation has prompted us to examine protein lysine succinylation in different mouse tissues in the presence and absence of SIRT5. Protein lysine succinylation predominantly accumulates in the heart when Sirt5 is deleted. Using proteomic studies, we have identified many cardiac proteins regulated by SIRT5. Our data suggest that ECHA, a protein involved in fatty acid oxidation, is a major enzyme that is regulated by SIRT5 and affects heart function. Sirt5 knockout (KO) mice have lower ECHA activity, increased long-chain acyl-CoAs, and decreased ATP in the heart under fasting conditions. Sirt5 KO mice develop hypertrophic cardiomyopathy, as evident from the increased heart weight relative to body weight, as well as reduced shortening and ejection fractions. These findings establish that regulating heart metabolism and function is amajor physiological function of lysine succinylation and SIRT5.

Protein post-translational modification (PTM) is a regulatory mechanism for protein activity modulation, localization, expression, and interactions with other cellular molecules. It involves the addition or removal of specific chemical groups on the amino acid residues of proteins. Its common forms include phosphorylation, ubiquitylation, methylation, and acetylation. Emerging research has highlighted lactylation, succinylation, and glycosylation. PTMs are involved in vital biological processes. The occurrence and development of diseases depends on protein abundance and is regulated by various PTMs. In addition, advancements in tumor immunotherapy have revealed that protein PTM is also involved in the proliferation, activation, and metabolic reprogramming of immune cells in tumor microenvironment. These PTMs play an important role in tumor immunotherapy. In this review, we comprehensively summarize the role of several types of PTMs in tumor immunotherapy. This review could provide new insights and future research directions for tumor immunotherapy.

Lysine succinylation, an important type of protein posttranslational modification, plays significant roles in many cellular processes. Accurate identification of succinylation sites can facilitate our understanding about the molecular mechanism and potential roles of lysine succinylation. However, even in well-studied systems, a majority of the succinylation sites remain undetected because the traditional experimental approaches to succinylation site identification are often costly, time-consuming, and laborious. In silico approach, on the other hand, is potentially an alternative strategy to predict succinylation substrates. In this paper, a novel computational predictor SuccinSite2.0 was developed for predicting generic and species-specific protein succinylation sites. This predictor takes the composition of profile-based amino acid and orthogonal binary features, which were used to train a random forest classifier. We demonstrated that the proposed SuccinSite2.0 predictor outperformed other currently existing implementations on a complementarily independent dataset. Furthermore, the important features that make visible contributions to species-specific and cross-species-specific prediction of protein succinylation site were analyzed. The proposed predictor is anticipated to be a useful computational resource for lysine succinylation site prediction. The integrated species-specific online tool of SuccinSite2.0 is publicly accessible.

Background Lysine succinylation is an emerging posttranslational modification that has garnered increased attention recently, but its role in gastric cancer (GC) remains underexplored. Methods Proteomic quantification of lysine succinylation was performed in human GC tissues and adjacent normal tissues by mass spectrometry. The mRNA and protein levels of lactate dehydrogenase A (LDHA) in GC and adjacent normal tissues were analyzed by qRT-PCR and western blot, respectively. The expression of K222-succinylated LDHA was measured in GC tissue microarray by the K222 succinylation-specific antibody. The interaction between LDHA and sequestosome 1 (SQSTM1) was measured by co-immunoprecipitation (co-IP) and proximity ligation assay (PLA). The binding of carnitine palmitoyltransferase 1A (CPT1A) to LDHA was determined by co-IP. The effect of K222-succinylated LDHA on tumor growth and metastasis was evaluated by in vitro and in vivo experiments. Results Altogether, 503 lysine succinylation sites in 303 proteins were identified. Lactate dehydrogenase A (LDHA), the key enzyme in Warburg effect, was found highly succinylated at K222 in GC. Intriguingly, this modification did not affect LDHA ubiquitination, but reduced the binding of ubiquitinated LDHA to SQSTM1, thereby decreasing its lysosomal degradation. We demonstrated that CPT1A functions as a lysine succinyltransferase that interacts with and succinylates LDHA. Moreover, high K222-succinylation of LDHA was associated with poor prognosis in patients with GC. Finally, overexpression of a succinylation-mimic mutant of LDHA promoted cell proliferation, invasion, and migration. Conclusions Our data revealed a novel lysosomal pathway of LDHA degradation, which is mediated by the binding of K63-ubiquitinated LDHA to SQSTM1. Strikingly, CPT1A succinylates LDHA on K222, which thereby reduces the binding and inhibits the degradation of LDHA, as well as promotes GC invasion and proliferation. This study thus uncovers a new role of lysine succinylation and the mechanism underlying LDHA upregulation in GC.

Gastric cancer (GC) is a malignancy of the lining of the stomach and is prone to distant metastasis, which involves a variety of complex molecules. The S100 proteins are a family of calcium‐binding cytosolic proteins that possess a wide range of intracellular and extracellular functions and play pivotal roles in the invasion and migration of tumour cells. Among these, S100A10 is known to be overexpressed in GC. Lysine succinylation, a recently identified form of protein post‐translational modification, is an important regulator of cellular processes. Here, we demonstrated that S100A10 was succinylated at lysine residue 47 (K47), and levels of succinylated S100A10 were increased in human GC. Moreover, K47 succinylation of S100A10 was stabilized by suppression of ubiquitylation and subsequent proteasomal degradation. Furthermore, carnitine palmitoyltransferase 1A (CPT1A) was found to function as a lysine succinyltransferase that interacts with S100A10. Succinylation of S100A10 is regulated by CPT1A, while desuccinylation is regulated by SIRT5. Overexpression of a succinylation mimetic mutant, K47E S100A10, increased cell invasion and migration. Taken together, this study reveals a novel mechanism of S100A10 accumulation mediated by succinylation in GC, which promotes GC progression and is regulated by the succinyltransferase CPT1A and SIRT5‐mediated desuccinylation.

Protein post‐translational modifications (PTMs) of histones are ubiquitous regulatory mechanisms involved in many biological processes, including replication, transcription, DNA damage repair and ontogenesis. Recently, many short‐chain acylation histone modifications have been identified by mass spectrometry (MS). Lysine succinylation (Ksuc or Ksucc) is a newly identified histone PTM that changes the chemical environment of histones and is similar to other acylation modifications; lysine succinylation appears to accumulate at transcriptional start sites and to correlate with gene expression. Although numerous studies are ongoing, there is a lack of reviews on the Ksuc of histones. Here, we review lysine succinylation sites on histones, including the chemical characteristics and the mechanism by which lysine succinylation influences nucleosomal structure, chromatin dynamics and several diseases and then discuss lysine succinylation regulation to identify theoretical and experimental proof of Ksuc on histones and in diseases to inspire further research into histone lysine succinylation as a target of disease treatment in the future.

Mitochondrial dysfunction and abnormal energy metabolism are major features of cancer. However, the mechanisms underlying mitochondrial dysfunction during cancer progression are far from being clarified. Here, it is demonstrated that the expression level of succinyl‐coenzyme A (CoA) synthetase GDP‐forming subunit β (SUCLG2) can affect the overall succinylation of lung adenocarcinoma (LUAD) cells. Succinylome analysis shows that the deletion of SUCLG2 can upregulate the succinylation level of mitochondrial proteins and inhibits the function of key metabolic enzymes by reducing either enzymatic activity or protein stability, thus dampening mitochondrial function in LUAD cells. Interestingly, SUCLG2 itself is also succinylated on Lys93, and this succinylation enhances its protein stability, leading to the upregulation of SUCLG2 and promoting the proliferation and tumorigenesis of LUAD cells. Sirtuin 5 (SIRT5) desuccinylates SUCLG2 on Lys93, followed by tripartite motif‐containing protein 21 (TRIM21)‐mediated ubiquitination through K63‐linkage and degradation in the lysosome. The findings reveal a new role for SUCLG2 in mitochondrial dysfunction and clarify the mechanism of the succinylation‐mediated protein homeostasis of SUCLG2 in LUAD, thus providing a theoretical basis for developing anti‐cancer drugs targeting SUCLG2. In LUAD, succinylation on Lys93 increases SUCLG2 stability, leading to metabolic reprogramming and tumor progression. SIRT5 desuccinylates SUCLG2 on Lys93, followed by TRIM21‐mediated ubiquitination through K63‐linkage and degradation in the lysosome, this leads to the upregulation of succinyl‐CoA and protein succinylation in the mitochondria and inhibits mitochondrial function. This study discovers a new function for SUCLG2 in tumor progression.

The aging of the central nervous system(CNS) is a primary contributor to neurodegenerative diseases in older individuals and significantly impacts their quality of life. Neuroinflammation, characterized by activation of microglia(MG) and release of cytokines, is closely associated with the onset of these neurodegenerative diseases. The activated status of MG is modulated by specifically programmed metabolic changes under various conditions. Succinylation, a novel post-translational modification(PTM) mainly involved in regulating mitochondrial energy metabolism pathways, remains unknown in its role in MG activation and aging. In the present study, we found that succinylation levels were significantly increased both during aging and upon lipopolysaccharide-induced(LPS-induced) MG activation undergoing metabolic reprogramming. Up-regulated succinylation induced by sirtuin 5 knockdown(Sirt5 KD) in microglial cell line BV2 resulted in significant up-regulation of aging-related genes, accompanied by impaired mitochondrial adaptability and a shift towards glycolysis as a major metabolic pathway. Furthermore, after LPS treatment, Sirt5 KD BV2 cells exhibited increased generation of reactive oxygen species(ROS), accumulation of lipid droplets, and elevated levels of lipid peroxidation. By employing immunoprecipitation, introducing point mutation to critical succinylation sites, and conducting enzyme activity assays for succinate dehydrogenase(SDH) and trifunctional enzyme subunit alpha(ECHA), we demonstrated that succinylation plays a regulatory role in modulating the activities of these mitochondrial enzymes. Finally, down-regulation the succinylation levels achieved through administration of succinyl phosphonate(SP) led to amelioration of MG senescence in vitro and neuroinflammation in vivo. To our knowledge, our data provide preliminary evidence indicating that up-regulated succinylation modifications elicit a senescence phenotype in MG through alterations in energy metabolism. Moreover, these findings suggest that manipulation of succinylation levels may offer valuable insights into the treatment of aging-related neuroinflammation. Graphical abstracts

Lysine succinylation is a post-translational modification that occurs when a succinyl group bonds with a lysine residue and changes the polarity of lysine from positive to negative, causing significant changes in the structure and functioning of proteins. Lysine succinylation occurs on various proteins and is crucial in the cellular and biological processes of eukaryotic and prokaryotic organisms. Succinylation site identification is an area of high research interest, and sequence-based prediction methods using machine learning and deep learning have been developed based on experimentally confirmed data of succinylation sites, aiming to be highly accurate, robust, quick, and cost-efficient. However, despite the usefulness of these methods, different issues must be addressed when building a model of lysine succinylation. As succinylation site predictors become more abundant, it is crucial to assess their advantages and drawbacks to identify potential issues and improve the efficiency of predicting succinylation sites. Among the multiple studies that have employed machine-learning and deep-learning applications, few have systematically examined computational issues. Hence, in this review, we summarize the challenges and restrictions in the development of succinylation prediction models and provide guidelines for more suitable and efficient computational methods.

Background Protein succinylation has recently emerged as an important and common post-translation modification (PTM) that occurs on lysine residues. Succinylation is notable both in its size (e.g., at 100 Da, it is one of the larger chemical PTMs) and in its ability to modify the net charge of the modified lysine residue from + 1 to − 1 at physiological pH. The gross local changes that occur in proteins upon succinylation have been shown to correspond with changes in gene activity and to be perturbed by defects in the citric acid cycle. These observations, together with the fact that succinate is generated as a metabolic intermediate during cellular respiration, have led to suggestions that protein succinylation may play a role in the interaction between cellular metabolism and important cellular functions. For instance, succinylation likely represents an important aspect of genomic regulation and repair and may have important consequences in the etiology of a number of disease states. In this study, we developed DeepSuccinylSite, a novel prediction tool that uses deep learning methodology along with embedding to identify succinylation sites in proteins based on their primary structure. Results Using an independent test set of experimentally identified succinylation sites, our method achieved efficiency scores of 79%, 68.7% and 0.48 for sensitivity, specificity and MCC respectively, with an area under the receiver operator characteristic (ROC) curve of 0.8. In side-by-side comparisons with previously described succinylation predictors, DeepSuccinylSite represents a significant improvement in overall accuracy for prediction of succinylation sites. Conclusion Together, these results suggest that our method represents a robust and complementary technique for advanced exploration of protein succinylation.