bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–03–23
fourteen papers selected by
Bruna Martins Garcia, CABIMER
  1. Protein succinylation mechanisms and potential targeted therapies in urinary disease.
  2. Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy.
  3. TPX2 lactylation is required for the cell cycle regulation and hepatocellular carcinoma progression.
  4. Turning sour into sweet: Lactylation modification as a promising target in cardiovascular health.
  5. Protocatechuic Acid Reduces Liver Fatty Acid Uptake in HFD-Fed Mice Associated With the Inhibition of DHHC5-Mediated CD36 Palmitoylation.
  6. In vitro reconstitution reveals substrate selectivity of protein S-acyltransferases.
  7. Genetic architecture of the red blood cell proteome in genetically diverse mice reveals central role of hemoglobin beta cysteine redox status in maintaining circulating glutathione pools.
  8. The roles of protein S-nitrosylation in regulating the growth and development of plants: A review.
  9. Nitric oxide production and protein S-nitrosation in algae.
  10. Histone lactylation enhances GCLC expression and thus promotes chemoresistance of colorectal cancer stem cells through inhibiting ferroptosis.
  11. Comprehensive analysis of the effects of P4ha1 and P4ha2 deletion on post-translational modifications of fibrillar collagens in mouse skin.
  12. Global Profiling of Lactylation Proteomics and Specific Lactylated Site Validation in Rheumatoid Arthritis Patients.
  13. Unraveling the metabolic‒epigenetic nexus: a new frontier in cardiovascular disease treatment.
  14. Understanding the structural and functional implications of lysine succinylation in Mycobacterium tuberculosis heat shock protein 16.3.
  1. Cell Signal. 2025 Mar 14. pii: S0898-6568(25)00157-3. [Epub ahead of print]131 111744
    Protein succinylation mechanisms and potential targeted therapies in urinary disease.
    Yuanquan Lou, Caitao Dong, Qinhong Jiang, Ziqi He, Sixing Yang.
      Succinylation is a relatively common post-translational modification. It occurs in the cytoplasm, mitochondria, and the nucleus, where its essential precursor, succinyl-CoA, is present, allowing for the modification of non-histone and histone proteins. In normal cells, succinylation levels are carefully regulated to sustain a dynamic balance, necessitating the involvement of various regulatory mechanisms, including non-enzymatic reactions, succinyltransferases, and desuccinylases. Among these regulatory factors, sirtuin 5, the first identified desuccinylase, plays a significant role and has been extensively researched. The level of succinylation has a significant effect on multiple metabolic pathways, including the tricarboxylic acid cycle, redox balance, and fatty acid metabolism. Dysregulated succinylation can contribute to the progression or exacerbation of various urinary diseases. Succinylation predominantly affects disease progression by altering the expression of key genes and modulating the activity of enzymes involved in vital metabolic processes. Desuccinylases primarily affect enzymes associated with Warburg's effect, thereby affecting the energy supply of tumor cells, while succinyltransferases can regulate gene transcription to alter cell phenotype, thereby involving the development of urinary diseases. Considering these effects, targeting succinylation-related enzymes to regulate metabolic pathways or gene expression may offer a promising therapeutic strategy for treating urinary diseases.
    Keywords:  Metabolic pathways; Post-translational modification; Succinylation; Targeted therapies; Urinary disease
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111744
  2. Exp Hematol Oncol. 2025 Mar 14. 14(1): 37
    Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy.
    Qiongjie Hu, Yueli Shi, Huang Wang, Liuwen Bing, Zhiyong Xu.
      Immunotherapy targeting immune checkpoints has gained traction across various cancer types in clinical settings due to its notable advantages. Despite this, the overall response rates among patients remain modest, alongside issues of drug resistance and adverse effects. Hence, there is a pressing need to enhance immune checkpoint blockade (ICB) therapies. Post-translational modifications (PTMs) are crucial for protein functionality. Recent research emphasizes their pivotal role in immune checkpoint regulation, directly impacting the expression and function of these key proteins. This review delves into the influence of significant PTMs-ubiquitination, phosphorylation, and glycosylation-on immune checkpoint signaling. By targeting these modifications, novel immunotherapeutic strategies have emerged, paving the way for advancements in optimizing immune checkpoint blockade therapies in the future.
    Keywords:  Cancer immunotherapy; Immune checkpoint blockade; Phosphorylation; Post-translational modifications; Ubiquitination
    DOI:  https://doi.org/10.1186/s40164-025-00627-6
  3. Life Sci Alliance. 2025 Jun;pii: e202402978. [Epub ahead of print]8(6):
    TPX2 lactylation is required for the cell cycle regulation and hepatocellular carcinoma progression.
    Shengzhi Liu, Jin Cai, Xiaoyu Qian, Junjiao Zhang, Yi Zhang, Xiang Meng, Mingjie Wang, Ping Gao, Xiuying Zhong.
      Targeting protein for Xklp2 (TPX2) is critical for mitosis and spindle assembly because of its control of Aurora kinase A (AURKA). However, the regulation of TPX2 activity and its subsequent effects on mitosis and cancer progression remain unclear. Here, we show that TPX2 is lactylated at K249 in hepatocellular carcinoma (HCC) tumour tissues and that this process is regulated by the lactylase CBP and the delactylase HDAC1. Lactate reduction via either shRNAs targeting lactate dehydrogenase A or the lactate dehydrogenase A inhibitor GSK2837808A decreases the level of TPX2 lactylation. Importantly, TPX2 lactylation is required for the cell cycle regulation and tumour growth. Mechanistically, TPX2 lactylation disrupts protein phosphatase 1 (PP1) binding to AURKA, enhances AURKA T288 phosphorylation, and facilitates the cell cycle progression. Overall, our study reveals a previously unappreciated role of TPX2 lactylation in regulating cell cycle progression and HCC tumorigenesis, exposing an important correlation between metabolic reprogramming and cell cycle regulation in HCC.
    DOI:  https://doi.org/10.26508/lsa.202402978
  4. Metabolism. 2025 Mar 18. pii: S0026-0495(25)00103-9. [Epub ahead of print] 156234
    Turning sour into sweet: Lactylation modification as a promising target in cardiovascular health.
    Yajie Liao, Liyan Niu, Jitao Ling, Yuzhen Cui, Zixuan Huang, Jingdong Xu, Yuan Jiang, Peng Yu, Xiao Liu.
      Lactylation, a recently identified posttranslational modification (PTM), has emerged as a critical regulatory mechanism in cardiovascular diseases (CVDs). This PTM involves the addition of lactyl groups to lysine residues on histones and nonhistone proteins, influencing gene expression and cellular metabolism. The discovery of lactylation has revealed new directions for understanding metabolic and immune processes, particularly in the context of CVDs. This review describes the intricate roles of specific lactylated proteins and enzymes, such as H3K18, HMGB1, MCT1/4, and LDH, in the regulation of cardiovascular pathology. This study also highlights the unique impact of lactylation on myocardial hypertrophy and distinguishes it from other PTMs, such as SUMOylation and acetylation, underscoring its potential as a therapeutic target. Emerging drugs targeting lactate transporters and critical enzymes involved in lactylation offer promising avenues for novel CVD therapies. This review calls for further research to elucidate the mechanisms linking lactylation to CVDs, emphasizing the need for comprehensive studies at the molecular, cellular, and organismal levels to pave the way for innovative preventive, diagnostic, and treatment strategies in cardiovascular medicine.
    Keywords:  Cardiovascular disease; Lactylation; Mechanism; Modification; Protein
    DOI:  https://doi.org/10.1016/j.metabol.2025.156234
  5. Mol Nutr Food Res. 2025 Mar 20. e70012
    Protocatechuic Acid Reduces Liver Fatty Acid Uptake in HFD-Fed Mice Associated With the Inhibition of DHHC5-Mediated CD36 Palmitoylation.
    Jia Li, Peiran Li, Xue Wu, Zibin Li, Yunlong Li, Chao Liu, Ji Bian, Lin Han, Min Wang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent and has emerged as a pressing issue for human health. A highly palmitoylated cluster of differentiation 36 (CD36) promotes free fatty acid (FFA) uptake, which contributes to the development of MASLD. Protocatechuic acid (PCA), the main metabolite of anthocyanins, was reported to inhibit MASLD by regulating the expression of CD36. However, the impact of PCA on CD36 palmitoylation has not been extensively studied. In the present study, we found that PCA could significantly reduce lipid uptake and accumulation in hepatocytes by decreasing CD36 palmitoylation. Inhibitors were used to prove that PCA suppressed CD36 palmitoylation by lowering zinc finger DHHC-type palmitoyltransferase 5 (DHHC5) palmitoylation, but not in an acyl protein thioesterase 1 (APT1)-dependent manner. Further experiments showed that PCA-mediated inhibition of DHHC5 palmitoylation and acyltransferase activity was closely related to the reduction of the CD36/Fyn/Lyn complex. PCA diminished the palmitoylation of CD36 and DHHC5 and ultimately lessened lipid uptake and accumulation in hepatocytes.
    Keywords:  CD36; DHHC5; metabolic dysfunction‐associated steatotic liver disease; palmitoylation; protocatechuic acid
    DOI:  https://doi.org/10.1002/mnfr.70012
  6. J Biol Chem. 2025 Mar 14. pii: S0021-9258(25)00255-8. [Epub ahead of print] 108406
    In vitro reconstitution reveals substrate selectivity of protein S-acyltransferases.
    Tanmay Mondal, James Song, Anirban Banerjee.
      Protein S-acylation, commonly known as protein palmitoylation, is the most prevalent form of protein lipidation with ∼6000 target proteins and in humans, is catalyzed by 23 integral membrane enzymes of the zDHHC family. Recognition of its importance in cellular physiology as well as human diseases has undergone an explosive growth in recent years. Yet, the nature of zDHHC-substrate interactions has remained poorly understood for most zDHHC enzymes. Cell-based experiments indicate a promiscuous and complex zDHHC-substrate network whereas lack of in vitro reconstitution experiments has impeded insights into the nature of discrete zDHHC-substrate interactions. Here we report a substrate S-acylation reconstitution assay, called the Pep-PAT assay, using purified enzyme and peptide fragments of substrates. We use the Pep-PAT assay to investigate the substrate S-acylation of three different zDHHC enzymes on seven different substrates. Remarkably, all the zDHHC enzymes showed robust activity with certain substrates but not others. These in vitro reconstitution experiments indicate that there is a preferred substrate hierarchy for zDHHC enzymes. We further used the Pep-PAT assay to interrogate the role of neighboring residues around the target cysteine on S-acylation of PSD-95 and SARS-CoV-2 Spike protein. Select residues around the target cysteines have distinct impact on substrate S-acylation, leading to the first insights into how neighboring residues around the target cysteine affect substrate S-acylation by zDHHC enzymes. Finally, we validated the impact of neighboring residues on substrate S-acylation using in cellulo assays. Our experiments build a framework for understanding substrate S-acylation by zDHHC enzymes.
    DOI:  https://doi.org/10.1016/j.jbc.2025.108406
  7. bioRxiv. 2025 Mar 04. pii: 2025.02.27.640676. [Epub ahead of print]
    Genetic architecture of the red blood cell proteome in genetically diverse mice reveals central role of hemoglobin beta cysteine redox status in maintaining circulating glutathione pools.
    Gregory R Keele, Monika Dzieciatkowska, Ariel M Hay, Matthew Vincent, Callan O'Connor, Daniel Stephenson, Julie A Reisz, Travis Nemkov, Kirk C Hansen, Grier P Page, James C Zimring, Gary A Churchill, Angelo D'Alessandro.
      Red blood cells (RBCs) transport oxygen but accumulate oxidative damage over time, reducing function in vivo and during storage-critical for transfusions. To explore genetic influences on RBC resilience, we profiled proteins, metabolites, and lipids from fresh and stored RBCs obtained from 350 genetically diverse mice. Our analysis identified over 6,000 quantitative trait loci (QTL). Compared to other tissues, prevalence of trans genetic effects over cis reflects the absence of de novo protein synthesis in anucleated RBCs. QTL hotspots at Hbb, Hba, Mon1a, and storage-specific Steap3 linked ferroptosis to hemolysis. Proteasome components clustered at multiple loci, underscoring the importance of degrading oxidized proteins. Post-translational modifications (PTMs) mapped predominantly to hemoglobins, particularly cysteine residues. Loss of reactive C93 in humanized mice (HBB C93A) disrupted redox balance, affecting glutathione pools, protein glutathionylation, and redox PTMs. These findings highlight genetic regulation of RBC oxidation, with implications for transfusion biology and oxidative stress-dependent hemolytic disorders.
    DOI:  https://doi.org/10.1101/2025.02.27.640676
  8. Int J Biol Macromol. 2025 Mar 17. pii: S0141-8130(25)02756-4. [Epub ahead of print]307(Pt 3): 142204
    The roles of protein S-nitrosylation in regulating the growth and development of plants: A review.
    Lijuan Wei, Junyi Zhao, Yue Zhong, Xiuqiao Wu, Shouhui Wei, Yiqing Liu.
      The free radical nitric oxide (NO) is an important redox-related signaling molecule modulating wide range of biological processes in all living plants. The transfer of NO bioactivity could be executed chiefly through a prototypic, redox-based post-translational modification, S-nitrosylation that covalently adds NO moiety to a reactive cysteine thiol of a target protein to form an S-nitrosothiol. Protein S-nitrosylation is recently emerged as an evolutionarily conserved and important mechanism regulating multiple aspects of plant growth and development. Here, we review the recent progress of S-nitrosylated proteins in the modulation of various plant development processes, including seed germination and aging, root development, seedling growth, flowering and fruit ripening and postharvest fruit quality. More importantly, the detailed function mechanism of proteins S-nitrosylation and key challenges in this field are also highlighted.
    Keywords:  Post-translational modification; Protein S-nitrosylation; S-nitrosoglutathione reductase
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142204
  9. Plant Sci. 2025 Mar 17. pii: S0168-9452(25)00090-1. [Epub ahead of print] 112472
    Nitric oxide production and protein S-nitrosation in algae.
    Zoé Chaudron, Valérie Nicolas-Francès, Carole Pichereaux, Siham Hichami, Claire Rosnoblet, Angelique Besson-Bard, David Wendehenne.
      Key roles for nitric oxide in signalling processes and plant physiological processes are now well established. In particular, the identification and functional characterisation of proteins regulated by S-nitrosation, a NO-dependent post-translational modification, provided remarkable insights into the subtle mechanisms by which NO mediates its effects. Nevertheless, and despite the considerable progress in understanding NO signalling, the question of how plant cells produce NO is not yet fully resolved. Interestingly, there is now compelling evidence that algae constitute promising biological models to investigate NO production and functions in plants. This article reviews recent highlights of research on NO production in algae and provides an overview of S-nitrosation in these organisms at the proteome level.
    Keywords:  Amidoxime Reducing Component; Klebsormidium nitens; S-nitrosation; algae; nitric oxide; nitric oxide synthase; signalling
    DOI:  https://doi.org/10.1016/j.plantsci.2025.112472
  10. Cell Death Dis. 2025 Mar 20. 16(1): 193
    Histone lactylation enhances GCLC expression and thus promotes chemoresistance of colorectal cancer stem cells through inhibiting ferroptosis.
    Jiao Deng, Yangkun Li, Lanlan Yin, Shuang Liu, Yanqi Li, Wancheng Liao, Lei Mu, Xuelai Luo, Jichao Qin.
      Colorectal cancer stem cells (CCSCs) play a critical role in mediating chemoresistance. Lactylation is a post-translational modification induced by lactate that regulates gene expression. However, whether lactylation affects the chemoresistance of CCSCs remains unknown. Here, we demonstrate that histone lactylation enhances CCSC chemoresistance both in vitro and in vivo. Furthermore, our findings showed that p300 catalyzes the lactylation of histone H4 at K12, whereas HDAC1 facilitates its delactylation in CCSCs. Notably, lactylation at H4K12 (H4K12la) upregulates GCLC expression and inhibits ferroptosis in CCSCs, and the inhibition of p300 or LDHA decreases H4K12la levels, thereby increasing the chemosensitivity of CCSCs. Additionally, the GCLC inhibitor BSO promotes ferroptosis and sensitizes CCSCs to oxaliplatin. Taken together, these findings suggest that histone lactylation upregulates GCLC to inhibit ferroptosis signaling, thus enhancing CCSC chemoresistance. These findings provide new insights into the relationship between cellular metabolism and chemoresistance and suggest potential therapeutic strategies targeting p300, LDHA, and GCLC. We showed that histones H4K12 lactylation promoted chemoresistance in CSCs. p300 catalyzes the lactylation of histone H4 at K12, HDAC1 inhibits the histone lactylation at the same site. H4K12la in CSCs regulates the expression of the ferroptosis-related gene GCLC, thereby inhibiting ferroptosis and leading to chemoresistance. Targeting the p300, LDHA, or GCLC may be overcome tumor chemoresistance.
    DOI:  https://doi.org/10.1038/s41419-025-07498-z
  11. Front Cell Dev Biol. 2025 ;13 1527839
    Comprehensive analysis of the effects of P4ha1 and P4ha2 deletion on post-translational modifications of fibrillar collagens in mouse skin.
    Vivek Sarohi.
       Introduction: Collagens, the most abundant proteins in mammals, play pivotal roles in maintaining tissue structure, functions, cell-to-cell communication, cellular migration, cellular behavior, and growth. Structures of collagens are highly complex due to the presence of dynamic post-translational modifications (PTMs), such as hydroxylations (on prolines and lysine residues) and O-glycosylation (on hydroxylysines) enzymatically catalyzed during biosynthesis in the endoplasmic reticulum. Collagen PTMs are essential for maintaining structural stability, elasticity, and different functions of collagens. The most prevalent modification in fibrillar collagens is prolyl 4-hydroxylation catalyzed by collagen prolyl 4-hydroxylases (C-P4Hs). Prolyl 4-hydroxylation on collagens plays a critical role in collagen biosynthesis, thermostability, and cell-collagen interactions. Collagens are large proteins. Different regions of collagen perform different functions, so the presence or absence of a PTM on a particular collagen site can affect its functioning. However, comprehensive site-specific identification of these PTMs on fibrillar collagen chains of mice skin has not been performed yet. Furthermore, the effects of prolyl 4-hydroxylase alpha 1 (P4HA1) and P4HA2 on 3-hydroxyproline, 5-hydroxylysine, and O-glycosylation sites of fibrillar collagen chains have not yet been explored.
    Methodology: This study presents a comprehensive PTM analysis of fibrillar collagen chains extracted from the skin of different mutants of C-P4Hs (P4ha1 +/- ; P4ha2-/-, P4ha1 +/+ ; P4ha2-/-, P4ha1 +/- ; P4ha2 +/- , P4ha1 +/+ ; P4ha2 +/- ) and wild-type mice. In this study, proteomics-based comprehensive PTM site identification by MS2 level ions from raw mass spectrometry data was performed, and MS1-level quantification was performed for PTM occupancy percentage analysis.
    Results and discussion: A total of 421 site-specific PTMs were identified on fibrillar collagen chains (COL1A1, COL1A2, and COL3A1) extracted from wild-type mice skin. A total of 23 P4HA1-specific and seven P4HA2-specific 4-hydroxyproline sites on fibrillar collagen chains were identified. Moreover, it was found that the P4ha1 and P4ha2 deletion can affect the 3-hydroxyproline occupancy percentages in mice skin. Interestingly, increased levels of lysyl 5-hydroxylation were detected upon partial deletion of P4ha1 and full deletion of P4ha2. These findings show that the effects of deletion of prolyl 4-hydroxylases are not limited to less 4-hydroxylation on some specific proline sites, but it can also modulate the prolyl 3-hydroxylation, lysyl 5-hydroxylation, and O-glycosylation occupancy percentages in the fibrillar collagen chains in a site-specific manner.
    Keywords:  O-glycosylation; collagen PTMs; lysyl 5-hydroxylation; prolyl 3-hydroxylation; prolyl 4-hydroxylation
    DOI:  https://doi.org/10.3389/fcell.2025.1527839
  12. J Proteome Res. 2025 Mar 20.
    Global Profiling of Lactylation Proteomics and Specific Lactylated Site Validation in Rheumatoid Arthritis Patients.
    Jiaqi Hu, Zhengyi Jin, Ying Gao, Qilong Liu, Yiyi Yu, Ruina Kong, Dongbao Zhao, Jie Gao.
      Protein lactylation is a novel post-translational modification that has rarely been investigated in rheumatoid arthritis (RA). This study aimed to explore lactylation proteomics in RA patients and validate sorted candidate lactylation sites. Synovial tissues from ten RA and six osteoarthritis (OA) patients were subjected to lactylation proteomics via affinity enrichment and LC-MS/MS. Four candidate lactylated modification sites were validated by immunoprecipitation. Totally, 566 sites and 250 proteins with lactylated modifications in RA patients and 548 sites and 220 proteins with lactylated modifications in OA patients were identified. By comparison, 24 upregulated but 2 downregulated lactylated modification sites and 18 upregulated but 1 downregulated lactylated modification protein were discovered in RA patients versus OA patients. The dysregulated lactylated proteins were mainly enriched in biological processes such as positive regulation of plasma membrane repair by GO analysis; pathways such as neutrophil extracellular trap formation by KEGG analysis; and two metabolism-related items by COG/KOG analysis. Immunoprecipitation confirmed that FTH1-K69la (P = 0007) and PKM2-K166la (P = 0.003), but not ANXA2-K115la (P = 0.127) or ANXA5-K76la (P = 0.361), were more abundant in RA patients versus OA patients. Moreover, FTH1-K69la was positively correlated with erythrocyte sedimentation rate (ESR) in RA patients (P = 0.037). Conclusively, this study describes a general landscape of lactylation proteomics in the RA.
    Keywords:  immunoprecipitation; lactylation proteomics; liquid chromatography-tandem mass spectrometry; post-translational modification; rheumatoid arthritis
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00680
  13. Cell Death Dis. 2025 Mar 18. 16(1): 183
    Unraveling the metabolic‒epigenetic nexus: a new frontier in cardiovascular disease treatment.
    Jun Ouyang, Deping Wu, Yumei Gan, Yuming Tang, Hui Wang, Jiangnan Huang.
      Cardiovascular diseases are the leading causes of death worldwide. However, there are still shortcomings in the currently employed treatment methods for these diseases. Therefore, exploring the molecular mechanisms underlying cardiovascular diseases is an important avenue for developing new treatment strategies. Previous studies have confirmed that metabolic and epigenetic alterations are often involved in cardiovascular diseases across patients. Moreover, metabolic and epigenetic factors interact with each other and affect the progression of cardiovascular diseases in a coordinated manner. Lactylation is a novel posttranslational modification (PTM) that links metabolism with epigenetics and affects disease progression. Therefore, analyzing the crosstalk between cellular metabolic and epigenetic factors in cardiovascular diseases is expected to provide insights for the development of new treatment strategies. The purpose of this review is to describe the relationship between metabolic and epigenetic factors in heart development and cardiovascular diseases such as heart failure, myocardial infarction, and atherosclerosis, with a focus on acylation and methylation, and to propose potential therapeutic measures.
    DOI:  https://doi.org/10.1038/s41419-025-07525-z
  14. Int J Biol Macromol. 2025 Mar 14. pii: S0141-8130(25)02598-X. [Epub ahead of print]307(Pt 3): 142046
    Understanding the structural and functional implications of lysine succinylation in Mycobacterium tuberculosis heat shock protein 16.3.
    Subhashree Barik, Kunal Shivaji Aldar, Ayon Chakraborty, Alok Kumar Panda, Rajiv K Kar, Ashis Biswas.
      Heat shock protein 16.3 (Hsp16.3), a major immunodominant antigen of Mycobacterium tuberculosis, exhibits molecular chaperone function that is essential for pathogen's survival and slow growth inside hosts, as well as for enhancing the efficacy of Bacillus Calmette-Guérin (BCG) vaccine. Proteomic studies revealed that Hsp16.3 undergoes lysine succinylation in vivo at all lysine residues (K47, K64, K78, K85, K114, K119 and K132) except K136. However, the effects of succinylation on its structure and function remain unexplored. This study investigated the impact of succinylation, induced by physiological (succinyl-CoA) and/or non-physiological (succinic anhydride) donors, on the structure, stability and chaperone function of Hsp16.3. Succinylation of all eight lysine residues, affirmed via fluorescamine assay and mass spectrometry, led to structural (secondary and tertiary) alterations, as indicated by circular dichroism (CD), fluorescence and in-silico analyses. Succinylation induced oligomeric dissociation (dodecamer to dimer) and enhanced surface hydrophobicity of Hsp16.3. Moreover, succinylation reduced protein stability, making it more conformationally flexible and less compact, as revealed by urea-denaturation, chymotrypsin-digestion and computational studies. Despite this reduced stability, succinylated Hsp16.3 exhibited enhanced chaperone activity, offering improved protection to stressed-prone client proteins. These findings provide useful insights into this modification, offering potential therapeutic avenues for targeting Hsp16.3 in M. tuberculosis infection.
    Keywords:  Chaperone function; Lysine succinylation; Mycobacterium tuberculosis Hsp16.3; Post-translational modification; Small heat shock proteins; Tuberculosis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142046
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