bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2024–06–23
23 papers selected by
Lakesh Kumar, BITS Pilani
  1. A pyruvate transporter in the apicoplast of apicomplexan parasites.
  2. N-acetylglucosamine supplementation fails to bypass the critical acetylation of glucosamine-6-phosphate required for Toxoplasma gondii replication and invasion.
  3. Comparison of the performance of SAG2, GRA6, and GRA7 for serological diagnosis of Toxoplasma gondii infection in cats.
  4. Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle.
  5. ToxoNet: A high confidence map of protein-protein interactions in Toxoplasma gondii.
  6. Altered landscape of total RNA, tRNA and sncRNA modifications in the liver and spleen of mice infected by Toxoplasma gondii.
  7. A novel DNA vaccine encoding the SRS13 protein administered by electroporation confers protection against chronic toxoplasmosis.
  8. Acetyl-CoA Synthetase Mutations S868G and V949I Do Not Confer Resistance to Antimalarial Drugs in vitro in Plasmodium falciparum.
  9. The Role of Neddylation in Malaria Parasites.
  10. Unlocking the Nexus of Sirtuins: A Comprehensive Review of Their Role in Skeletal Muscle Metabolism, Development, and Disorders.
  11. 2-(Methyl(phenyl)amino)-N-(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition.
  12. Exploring the uncharted territory of the potential protein-protein interactions of cytosolic malate dehydrogenase.
  13. Malate dehydrogenase in plants: evolution, structure, and a myriad of functions.
  14. Metabolic regulation of misfolded protein import into mitochondria.
  15. Manipulating mitochondrial pyruvate carrier function causes metabolic remodeling in corneal myofibroblasts that ameliorates fibrosis.
  16. AtSRT1 regulates flowering by regulating flowering integrators and energy signals in Arabidopsis.
  17. AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.
  18. Advances in Organic Fluorescent Probes for Intracellular Zn2+ Detection and Bioimaging.
  19. Beyond histones: the elusive substrates of chromatin regulators.
  20. H3K56 acetylation affects Candida albicans morphology and secreted soluble factors interacting with the host.
  21. The role of metabolic reprogramming in kidney cancer.
  22. LYSINE METHYLTRANSFERASE 2 PLAYS A KEY ROLE IN THE ENCYSTATION PROCESS IN THE PARASITE Giardia lamblia.
  23. Advances in the interaction of glycolytic reprogramming with lactylation.
  1. Proc Natl Acad Sci U S A. 2024 Jun 18. 121(25): e2314314121
    A pyruvate transporter in the apicoplast of apicomplexan parasites.
    Pu Chen, Yukun Chen, Ningbo Xia, Bolin Fan, Zhipeng Niu, Zhengming He, Xu Wang, Jing Yuan, Nishith Gupta, Bang Shen.
      Pyruvate lies at a pivotal node of carbon metabolism in eukaryotes. It is involved in diverse metabolic pathways in multiple organelles, and its interorganelle shuttling is crucial for cell fitness. Many apicomplexan parasites harbor a unique organelle called the apicoplast that houses metabolic pathways like fatty acid and isoprenoid precursor biosyntheses, requiring pyruvate as a substrate. However, how pyruvate is supplied in the apicoplast remains enigmatic. Here, deploying the zoonotic parasite Toxoplasma gondii as a model apicomplexan, we identified two proteins residing in the apicoplast membranes that together constitute a functional apicoplast pyruvate carrier (APC) to mediate the import of cytosolic pyruvate. Depletion of APC results in reduced activities of metabolic pathways in the apicoplast and impaired integrity of this organelle, leading to parasite growth arrest. APC is a pyruvate transporter in diverse apicomplexan parasites, suggesting a common strategy for pyruvate acquisition by the apicoplast in these clinically relevant intracellular pathogens.
    Keywords:  MEP pathway; Toxoplasma; chloroplast; fatty acid synthesis; isoprenoids
    DOI:  https://doi.org/10.1073/pnas.2314314121
  2. PLoS Pathog. 2024 Jun 20. 20(6): e1011979
    N-acetylglucosamine supplementation fails to bypass the critical acetylation of glucosamine-6-phosphate required for Toxoplasma gondii replication and invasion.
    María Pía Alberione, Víctor González-Ruiz, Olivier von Rohr, Serge Rudaz, Dominique Soldati-Favre, Luis Izquierdo, Joachim Kloehn.
      The cell surface of Toxoplasma gondii is rich in glycoconjugates which hold diverse and vital functions in the lytic cycle of this obligate intracellular parasite. Additionally, the cyst wall of bradyzoites, that shields the persistent form responsible for chronic infection from the immune system, is heavily glycosylated. Formation of glycoconjugates relies on activated sugar nucleotides, such as uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). The glucosamine-phosphate-N-acetyltransferase (GNA1) generates N-acetylglucosamine-6-phosphate critical to produce UDP-GlcNAc. Here, we demonstrate that downregulation of T. gondii GNA1 results in a severe reduction of UDP-GlcNAc and a concomitant drop in glycosylphosphatidylinositols (GPIs), leading to impairment of the parasite's ability to invade and replicate in the host cell. Surprisingly, attempts to rescue this defect through exogenous GlcNAc supplementation fail to completely restore these vital functions. In depth metabolomic analyses elucidate diverse causes underlying the failed rescue: utilization of GlcNAc is inefficient under glucose-replete conditions and fails to restore UDP-GlcNAc levels in GNA1-depleted parasites. In contrast, GlcNAc-supplementation under glucose-deplete conditions fully restores UDP-GlcNAc levels but fails to rescue the defects associated with GNA1 depletion. Our results underscore the importance of glucosamine-6-phosphate acetylation in governing T. gondii replication and invasion and highlight the potential of the evolutionary divergent GNA1 in Apicomplexa as a target for the development of much-needed new therapeutic strategies.
    DOI:  https://doi.org/10.1371/journal.ppat.1011979
  3. Front Vet Sci. 2024 ;11 1423581
    Comparison of the performance of SAG2, GRA6, and GRA7 for serological diagnosis of Toxoplasma gondii infection in cats.
    Serges Sabukunze, Haorong Gu, Lin Zhao, Honglin Jia, Huanping Guo.
      Toxoplasmosis is an important zoonotic disease caused by Toxoplasma gondii that can infect almost all warm-blooded animals worldwide, including humans. The high prevalence of T. gondii infection and its ability to cause serious harm to humans and animals, especially immunodeficient individuals, make it a key public health issue. Accurate diagnostic tools with high sensitivity are needed for controlling T. gondii infection. In the current study, we compared the performance of recombinant SAG2, GRA6, and GRA7 in ELISA for the serological diagnosis of T. gondii infection in cats. We further investigated the antigenicity of recombinant dense granule protein 3 (rGRA3), rGRA5, rGRA8, and rSRS29A expressed in a plant-based, cell-free expression system for detecting antibodies in T. gondii-infected cats. In summary, our data suggest that GRA7 is more sensitive than the other two antigens for the serodiagnosis of T. gondii infection in cats, and GRA3 expressed in the cell-free system is also a priming antigen in serological tests for detecting T. gondii infection in cats.
    Keywords:  GRA3; GRA6; GRA7; SAG2; Toxoplasma gondii; cats; serodiagnosis
    DOI:  https://doi.org/10.3389/fvets.2024.1423581
  4. Int J Mol Sci. 2024 Jun 02. pii: 6145. [Epub ahead of print]25(11):
    Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle.
    Evelin Schwarzer, Oleksii Skorokhod.
      Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of Plasmodium spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host.
    Keywords:  Plasmodium; acetylation; glutathionylation; glycosylation; lipidation; lipoxidation; methylation; mosquito Anopheles; phosphorylation; ubiquitination
    DOI:  https://doi.org/10.3390/ijms25116145
  5. PLoS Comput Biol. 2024 Jun 20. 20(6): e1012208
    ToxoNet: A high confidence map of protein-protein interactions in Toxoplasma gondii.
    Lakshmipuram S Swapna, Grant C Stevens, Aline Sardinha-Silva, Lucas Zhongming Hu, Verena Brand, Daniel D Fusca, Cuihong Wan, Xuejian Xiong, Jon P Boyle, Michael E Grigg, Andrew Emili, John Parkinson.
      The apicomplexan intracellular parasite Toxoplasma gondii is a major food borne pathogen that is highly prevalent in the global population. The majority of the T. gondii proteome remains uncharacterized and the organization of proteins into complexes is unclear. To overcome this knowledge gap, we used a biochemical fractionation strategy to predict interactions by correlation profiling. To overcome the deficit of high-quality training data in non-model organisms, we complemented a supervised machine learning strategy, with an unsupervised approach, based on similarity network fusion. The resulting combined high confidence network, ToxoNet, comprises 2,063 interactions connecting 652 proteins. Clustering identifies 93 protein complexes. We identified clusters enriched in mitochondrial machinery that include previously uncharacterized proteins that likely represent novel adaptations to oxidative phosphorylation. Furthermore, complexes enriched in proteins localized to secretory organelles and the inner membrane complex, predict additional novel components representing novel targets for detailed functional characterization. We present ToxoNet as a publicly available resource with the expectation that it will help drive future hypotheses within the research community.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012208
  6. PLoS Negl Trop Dis. 2024 Jun 21. 18(6): e0012281
    Altered landscape of total RNA, tRNA and sncRNA modifications in the liver and spleen of mice infected by Toxoplasma gondii.
    Xiao-Xuan Zhang, Yu-Zhe Sun, Wei Wang, Yang Gao, Xin-Yu Wei, Hong-Chao Sun, Chun-Ren Wang, Hong-Bo Ni, Xing Yang, Hany M Elsheikha, Huan-Ping Guo.
       BACKGROUND: Pathogens can impact host RNA modification machinery to establish a favorable cellular environment for their replication. In the present study, we investigated the effect of Toxoplasma gondii infection on host RNA modification profiles and explored how these modifications may influence the host-parasite interaction.
    METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the modification levels of ∼ 80 nt tRNA and 17-50 nt sncRNAs in mouse liver, spleen, and serum using liquid chromatography and tandem mass spectrometry analysis. The results revealed alterations in RNA modification profiles, particularly during acute infection. The liver exhibited more differentially abundant RNA modifications than the spleen. RNA modification levels in serum were mostly downregulated during acute infection compared to control mice. Correlations were detected between different RNA modifications in the liver and spleen during infection and between several RNA modifications and many cytokines. Alterations in RNA modifications affected tRNA stability and protein translation.
    CONCLUSIONS/SIGNIFICANCE: These findings provide new insight into the role of RNA modifications in mediating the murine host response to T. gondii infection.
    DOI:  https://doi.org/10.1371/journal.pntd.0012281
  7. Vaccine. 2024 Jun 15. pii: S0264-410X(24)00706-0. [Epub ahead of print]
    A novel DNA vaccine encoding the SRS13 protein administered by electroporation confers protection against chronic toxoplasmosis.
    Ceren Gül, Aytül Gül, Tuğba Karakavuk, Sedef Erkunt Alak, Muhammet Karakavuk, Hüseyin Can, Aysu Değirmenci Döşkaya, İrem Yavuz, Seren Kaplan, Gülşah Erel Akbaba, Didem Şen Karaman, Hasan Akbaba, Ahmet Efe Köseoğlu, Tolga Ovayurt, Adnan Yüksel Gürüz, Cemal Ün, Ayşe Gülten Kantarcı, Mert Döşkaya.
      Toxoplasma gondii is an obligate intracellular parasite that can infect a variety of mammals including humans and causes toxoplasmosis. Unfortunately, a protective and safe vaccine against toxoplasmosis hasn't been developed yet. In this study, we developed a DNA vaccine encoding the SRS13 protein and immunized BALB/c mice thrice with pVAX1-SRS13 through the intramuscular route (IM) or intradermally using an electroporation device (ID + EP). The immunogenicity of pVAX1-SRS13 was analyzed by ELISA, Western blot, cytokine ELISA, and flow cytometry. The protective efficacy of the pVAX1-SRS13 was investigated by challenging mice orally with T. gondii PRU strain tissue cysts. The results revealed that pVAX1-SRS13 administered through IM or ID + EP routes induced high level of anti-SRS13 IgG antibody responses (P = 0.0037 and P < 0.0001). The IFN-γ level elicited by the pVAX1-SRS13 (ID + EP) was significantly higher compared to the control group (P = 0.00159). In mice administered with pVAX1-SRS13 (ID + EP), CD8+ cells secreting IFN-γ was significantly higher compared to pVAX1-SRS13 (IM) (P = 0.0035) and the control group (P = 0.0068). Mice vaccinated with the SRS13 DNA vaccine did not induce significant IL-4 level. Moreover, a significant reduction in the number of tissue cysts and the load of T. gondii DNA was detected in brains of mice administered with pVAX1-SRS13 through ID + EP and IM routes compared to controls. In conclusion, the SRS13 DNA vaccine was found to be highly immunogenic and confers strong protection against chronic toxoplasmosis.
    Keywords:  DNA vaccine; Electroporation; SRS13; T. gondii PRU strain; Toxoplasma gondii; Toxoplasmosis
    DOI:  https://doi.org/10.1016/j.vaccine.2024.06.032
  8. bioRxiv. 2024 Jun 04. pii: 2024.06.03.597226. [Epub ahead of print]
    Acetyl-CoA Synthetase Mutations S868G and V949I Do Not Confer Resistance to Antimalarial Drugs in vitro in Plasmodium falciparum.
    Wei Zhao, Zheng Xiang, Weilin Zeng, Yucheng Qin, Maohua Pan, Yanrui Wu, Mengxi Duan, Ye Mou, Tao Liang, Yanmei Zhang, Cheng Liu, Xiuya Tang, Yaming Huang, Gongchao Yang, Liwang Cui, Zhaoqing Yang.
      Plasmodium falciparum acetyl-CoA synthetase (PfACAS) protein is an important source of acetyl-CoA. We detected the mutations S868G and V949I in PfACAS by whole-genome sequencing analysis in some recrudescent parasites after antimalarial treatment with artesunate and dihydroartemisinin-piperaquine, suggesting that they may confer drug resistance. Using CRISPR/Cas9 technology, we engineered parasite lines carrying the PfACAS S868G and V949I mutations in two genetic backgrounds and evaluated their susceptibility to antimalarial drugs in vitro. The results demonstrated that PfACAS S868G and V949I mutations alone or in combination were not enough to provide resistance to antimalarial drugs.
    DOI:  https://doi.org/10.1101/2024.06.03.597226
  9. DNA Cell Biol. 2024 Jun 17.
    The Role of Neddylation in Malaria Parasites.
    Plabita Paul, Bandita Nayak, Satish Mishra.
      Plasmodium parasites, the causative agents of malaria, rely on sophisticated cellular mechanisms to survive and proliferate within their hosts. Plasmodium complex life cycle requires posttranslational modifications (PTMs) to control cellular activities. Neddylation is a type of PTM in which NEDD8 is covalently attached to target proteins and plays an important role in cell cycle control and metabolism. Covalent attachment to its substrates requires the Nedd8-activating enzyme, E1; the NEDD8-conjugating enzyme, E2; and the ligase, E3. In Plasmodium, protein neddylation is essential for parasite development during the stage I-II transition from zygote to ookinete differentiation and malaria transmission. Here, we discuss the current understanding of protein neddylation in Plasmodium, which is involved in malaria transmission.
    Keywords:  Nedd8; Plasmodium; malaria; neddylation; transmission
    DOI:  https://doi.org/10.1089/dna.2024.0120
  10. Int J Biol Sci. 2024 ;20(8): 3219-3235
    Unlocking the Nexus of Sirtuins: A Comprehensive Review of Their Role in Skeletal Muscle Metabolism, Development, and Disorders.
    Bahareldin Ali Abdalla Gibril, Xinwei Xiong, Xuewen Chai, Qiao Xu, Jishang Gong, Jiguo Xu.
      The sirtuins constitute a group of histone deacetylases reliant on NAD+ for their activity that have gained recognition for their critical roles as regulators of numerous biological processes. These enzymes have various functions in skeletal muscle biology, including development, metabolism, and the body's response to disease. This comprehensive review seeks to clarify sirtuins' complex role in skeletal muscle metabolism, including glucose uptake, fatty acid oxidation, mitochondrial dynamics, autophagy regulation, and exercise adaptations. It also examines their critical roles in developing skeletal muscle, including myogenesis, the determination of muscle fiber type, regeneration, and hypertrophic responses. Moreover, it sheds light on the therapeutic potential of sirtuins by examining their impact on a range of skeletal muscle disorders. By integrating findings from various studies, this review outlines the context of sirtuin-mediated regulation in skeletal muscle, highlighting their importance and possible consequences for health and disease.
    Keywords:  development; disorders; sirtuins; skeletal muscle metabolism
    DOI:  https://doi.org/10.7150/ijbs.96885
  11. Drug Dev Res. 2024 Jun;85(4): e22224
    2-(Methyl(phenyl)amino)-N-(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition.
    Selen Gozde Kaya, Gokcen Eren, Alberto Massarotti, Filiz Bakar-Ates, Erva Ozkan, Mahmut Gozelle, Yesim Ozkan.
      The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD+-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61-ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC50 values of 9.97, 5.74, and 8.92 μM, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.
    Keywords:  MCF‐7; optimization; selectivity; sirtuin; α‐tubulin
    DOI:  https://doi.org/10.1002/ddr.22224
  12. Essays Biochem. 2024 Jun 13. pii: EBC20230083. [Epub ahead of print]
    Exploring the uncharted territory of the potential protein-protein interactions of cytosolic malate dehydrogenase.
    Joseph J Provost, Amy D Parente, Kristin M Slade, Thomas J Wiese.
      In this review, we examine the protein-protein interactions of cytosolic malate dehydrogenase (MDH), an under-studied area in cellular metabolism. We provide a comprehensive overview of MDH involvement in metabolism, especially its interactions with metabolic partners and dynamics of changing metabolism. We present an analysis of the biophysical nature of these interactions and the current methods used to study them. Our review includes an assessment of computational docking studies, which offer initial hypotheses about potential MDH interaction partners. Furthermore, we provide a summary of the sparse yet insightful experimental evidence available, establishing a foundation for future research. By integrating biophysical analysis and methodological advancements, this paper aims to illuminate the intricate network of interactions involving cytosolic MDH and their metabolic implications. This work not only contributes to our understanding of MDH's role in metabolism but also highlights the potential impact of these interactions in metabolic disorders.
    Keywords:  Malate dehydrogenase; carbohydrate metabolism; cytosol; protein-protein interactions
    DOI:  https://doi.org/10.1042/EBC20230083
  13. Essays Biochem. 2024 Jun 13. pii: EBC20230089. [Epub ahead of print]
    Malate dehydrogenase in plants: evolution, structure, and a myriad of functions.
    Lisa M Baird, Christopher E Berndsen, Jonathan D Monroe.
      Malate dehydrogenase (MDH) catalyzes the interconversion of oxaloacetate and malate coupled to the oxidation/reduction of coenzymes NAD(P)H/NAD(P)+. While most animals have two isoforms of MDH located in the cytosol and mitochondria, all major groups of land plants have at least six MDHs localized to the cytosol, mitochondria, plastids, and peroxisomes. This family of enzymes participates in important reactions in plant cells including photosynthesis, photorespiration, lipid metabolism, and NH4+ metabolism. MDH also helps to regulate the energy balance in the cell and may help the plant cope with various environmental stresses. Despite their functional diversity, all of the plant MDH enzymes share a similar structural fold and act as dimers. In this review, we will introduce readers to our current understanding of the plant MDHs, including their evolution, structure, and function. The focus will be on the MDH enzymes of the model plant Arabidopsis thaliana.
    Keywords:  evolutionary biology; malate dehydrogenase; plant biology; protein structure; redox balance
    DOI:  https://doi.org/10.1042/EBC20230089
  14. Elife. 2024 Jun 20. pii: RP87518. [Epub ahead of print]12
    Metabolic regulation of misfolded protein import into mitochondria.
    Yuhao Wang, Linhao Ruan, Jin Zhu, Xi Zhang, Alexander Chih-Chieh Chang, Alexis Tomaszewski, Rong Li.
      Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the 'mitochondria as guardian in cytosol' (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.
    Keywords:  AMPK; MAGIC; S. cerevisiae; cell biology; human; metabolism; misfolded protein; mitochondria; protein import; proteostasis
    DOI:  https://doi.org/10.7554/eLife.87518
  15. Redox Biol. 2024 Jun 08. pii: S2213-2317(24)00213-1. [Epub ahead of print]75 103235
    Manipulating mitochondrial pyruvate carrier function causes metabolic remodeling in corneal myofibroblasts that ameliorates fibrosis.
    Kye-Im Jeon, Ankita Kumar, Paul S Brookes, Keith Nehrke, Krystel R Huxlin.
      Myofibroblasts are key cellular effectors of corneal wound healing from trauma, surgery, or infection. However, their persistent deposition of disorganized extracellular matrix can also cause corneal fibrosis and visual impairment. Recent work showed that the PPARγ agonist Troglitazone can mitigate established corneal fibrosis, and parallel in vitro data suggested this occurred through inhibition of the mitochondrial pyruvate carrier (MPC) rather than PPARγ. In addition to oxidative phosphorylation (Ox-Phos), pyruvate and other mitochondrial metabolites provide carbon for the synthesis of biological macromolecules. However, it is currently unclear how these roles selectively impact fibrosis. Here, we performed bioenergetic, metabolomic, and epigenetic analyses of corneal fibroblasts treated with TGF-β1 to stimulate myofibroblast trans-differentiation, with further addition of Troglitazone or the MPC inhibitor UK5099, to identify MPC-dependencies that may facilitate remodeling and loss of the myofibroblast phenotype. Our results show that a shift in energy metabolism is associated with, but not sufficient to drive cellular remodeling. Metabolites whose abundances were sensitive to MPC inhibition suggest that sustained carbon influx into the Krebs' cycle is prioritized over proline synthesis to fuel collagen deposition. Furthermore, increased abundance of acetyl-CoA and increased histone H3 acetylation suggest that epigenetic mechanisms downstream of metabolic remodeling may reinforce cellular phenotypes. Overall, our results highlight a novel molecular target and metabolic vulnerability that affects myofibroblast persistence in the context of corneal wounding.
    Keywords:  Cornea; Fibrosis; Metabolomics; Mitochondria; Pyruvate
    DOI:  https://doi.org/10.1016/j.redox.2024.103235
  16. Plant Physiol Biochem. 2024 Jun 14. pii: S0981-9428(24)00509-6. [Epub ahead of print]213 108841
    AtSRT1 regulates flowering by regulating flowering integrators and energy signals in Arabidopsis.
    Ping Wang, Lufang Su, Lan Cao, Hanbing Hu, Heping Wan, Chunhong Wu, Yu Zheng, Chun Bao, Xiaoyun Liu.
      Epigenetic modifications, such as histone alterations, play crucial roles in regulating the flowering process in Arabidopsis, a typical long-day model plant. Histone modifications are notably involved in the intricate regulation of FLC, a key inhibitor of flowering. Although sirtuin-like protein and NAD+-dependent deacetylases play an important role in regulating energy metabolism, plant stress responses, and hormonal signal transduction, the mechanisms underlying their developmental transitions remain unclear. Thus, this study aimed to reveal how Arabidopsis NAD + -dependent deacetylase AtSRT1 affects flowering by regulating the expression of flowering integrators. Genetic and molecular evidence demonstrated that AtSRT1 mediates histone deacetylation by directly binding near the transcriptional start sites (TSS) of the flowering integrator genes FT and SOC1 and negatively regulating their expression by modulating the expression of the downstream gene LFY to inhibit flowering. Additionally, AtSRT1 directly down-regulates the expression of TOR, a glucose-driven central hub of energy signaling, which controls cell metabolism and growth in response to nutritional and environmental factors. This down-regulation occurs through binding near the TSS of TOR, facilitating the addition of H3K27me3 marks on FLC via the TOR-FIE-PRC2 pathway, further repressing flowering. These results uncover a multi-pathway regulatory network involving deacetylase AtSRT1 during the flowering process, highlighting its interaction with TOR as a hub for the coordinated regulation of energy metabolism and flowering initiation. These findings significantly enhance understanding of the complexity of histone modifications in the regulation of flowering.
    Keywords:  AtSRT1; FLC; FT; Flowering; SOC1; TOR‐FIE‐PRC2
    DOI:  https://doi.org/10.1016/j.plaphy.2024.108841
  17. Cell Res. 2024 Jun 19.
    AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.
    Mengqi Li, Yu Wang, Xiaoyan Wei, Wei-Feng Cai, Jianfeng Wu, Mingxia Zhu, Yongliang Wang, Yan-Hui Liu, Jinye Xiong, Qi Qu, Yan Chen, Xiao Tian, Luming Yao, Renxiang Xie, Xiaomin Li, Siwei Chen, Xi Huang, Cixiong Zhang, Changchuan Xie, Yaying Wu, Zheni Xu, Baoding Zhang, Bin Jiang, Zhi-Chao Wang, Qinxi Li, Gang Li, Shu-Yong Lin, Li Yu, Hai-Long Piao, Xianming Deng, Jiahuai Han, Chen-Song Zhang, Sheng-Cai Lin.
      The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.
    DOI:  https://doi.org/10.1038/s41422-024-00985-6
  18. Molecules. 2024 May 28. pii: 2542. [Epub ahead of print]29(11):
    Advances in Organic Fluorescent Probes for Intracellular Zn2+ Detection and Bioimaging.
    Yi Chen.
      Zinc ions (Zn2+) play a key role in maintaining and regulating protein structures and functions. To better understand the intracellular Zn2+ homeostasis and signaling role, various fluorescent sensors have been developed that allow the monitoring of Zn2+ concentrations and bioimaging in live cells in real time. This review highlights the recent development of organic fluorescent probes for the detection and imaging of intracellular Zn2+, including the design and construction of the probes, fluorescent response mechanisms, and their applications to intracellular Zn2+ detection and imaging on-site. Finally, the current challenges and prospects are discussed.
    Keywords:  detection; fluorescent probe; imaging; intracellular Zn2+
    DOI:  https://doi.org/10.3390/molecules29112542
  19. Genes Dev. 2024 Jun 12.
    Beyond histones: the elusive substrates of chromatin regulators.
    Mattias Mannervik.
      Gene transcription is intimately linked to chromatin state and histone modifications. However, the enzymes mediating these post-translational modifications have many additional, nonhistone substrates, making it difficult to ascribe the most relevant modification. In this issue of Genes & Development, Crain and colleagues (doi:10.1101/gad.351698.124) have combined a powerful histone replacement system with mutational analysis of a chromatin regulator and a chromatin reader in Drosophila melanogaster Importantly, they discovered that genes controlled by the histone 4 lysine 20 (H4K20) methyltransferase Set8 and the protein recognizing H4K20 monomethylation, L(3)mbt, differ substantially from those affected by mutation of H4K20 itself. This demonstrates that H4K20 is not the key substrate for Set8 but that methylation of other, unidentified proteins mediates its effects on transcription.
    Keywords:  Drosophila melanogaster; H4K20me1; L(3)mbt; Set8; chromatin; epigenetics; gene expression; genomics
    DOI:  https://doi.org/10.1101/gad.351969.124
  20. Biochim Biophys Acta Gene Regul Mech. 2024 Jun 15. pii: S1874-9399(24)00044-0. [Epub ahead of print] 195048
    H3K56 acetylation affects Candida albicans morphology and secreted soluble factors interacting with the host.
    Marisa Conte, Daniela Eletto, Martina Pannetta, Roberta Esposito, Maria Chiara Monti, Elva Morretta, Peter Tessarz, Silvana Morello, Alessandra Tosco, Amalia Porta.
      In recent years, epigenetics has been revealed as a mechanism able to modulate the expression of virulence traits in diverse pathogens, including Candida albicans. Indeed, epigenetic regulation can sense environmental changes, leading to the rapid and reversible modulation of gene expression with consequent adaptation to novel environments. How epigenetic changes can impact expression and signalling output, including events associated with mechanisms of morphological transition and virulence, is still poorly studied. Here, using nicotinamide as a sirtuin inhibitor, we explored how the accumulation of the H3K56 acetylation, the most prominent histone acetylation in C. albicans, might affect its interaction with the host. Our experiments demonstrate that H3K56 acetylation profoundly affects the production and/or secretion of soluble factors compromising actin remodelling and cytokine production. ChIP- and RNA-seq analyses highlighted a direct impact of H3K56 acetylation on genes related to phenotypic switching, biofilm formation and cell aggregation. Direct and indirect regulation also involves genes related to cell wall protein biosynthesis, β-glucan and mannan exposure, and hydrolytic secreted enzymes, supporting the hypothesis that the fluctuations of H3K56 acetylation in C. albicans might impair the macrophage response to the yeast and thus promote the host-immune escaping.
    Keywords:  Candida albicans; ChIP-seq; Farnesol; H3K56 acetylation; Macrophage response; RNA-seq
    DOI:  https://doi.org/10.1016/j.bbagrm.2024.195048
  21. Front Oncol. 2024 ;14 1402351
    The role of metabolic reprogramming in kidney cancer.
    Ziyi Chen, Xiaohong Zhang.
      Metabolic reprogramming is a cellular process in which cells modify their metabolic patterns to meet energy requirements, promote proliferation, and enhance resistance to external stressors. This process also introduces new functionalities to the cells. The 'Warburg effect' is a well-studied example of metabolic reprogramming observed during tumorigenesis. Recent studies have shown that kidney cells undergo various forms of metabolic reprogramming following injury. Moreover, metabolic reprogramming plays a crucial role in the progression, prognosis, and treatment of kidney cancer. This review offers a comprehensive examination of renal cancer, metabolic reprogramming, and its implications in kidney cancer. It also discusses recent advancements in the diagnosis and treatment of renal cancer.
    Keywords:  amino acid metabolism; glucose metabolism; metabolism reprogramming; renal cancer; treatment
    DOI:  https://doi.org/10.3389/fonc.2024.1402351
  22. Acta Trop. 2024 Jun 19. pii: S0001-706X(24)00177-3. [Epub ahead of print] 107295
    LYSINE METHYLTRANSFERASE 2 PLAYS A KEY ROLE IN THE ENCYSTATION PROCESS IN THE PARASITE Giardia lamblia.
    Luciano Díaz-Pérez, Agostina Salusso, Rocío Patolsky, Gonzalo Mayol, Gonzalo Quasollo, Constanza Feliziani, María Carolina Touz, Andrea S Rópolo.
      Histone post-translational modifications are extensively studied for their role in regulating gene transcription and cellular environmental adaptation. Research into these modifications has recently begun in the protozoan parasite Giardia lamblia, focusing on histone-modifying enzymes and specific post-translational changes. In the transformation from the trophozoite to the cyst form in the life cycle of this parasite, significant morphological and genetic alterations occur, culminating in the synthesis of cyst wall proteins responsible for forming the protective cyst wall. It has been previously demonstrated that histone deacetylation is required during encystation and that the enzyme lysine methyltransferase 1 is involved in the upregulation of encystation. Our study aims to extend the analysis to lysine methyltransferase 2 (GlKMT2) function. For this, two constructs were generated: one that downregulate the expression of GLKMT2 via antisense (glkmt2-as transgenic cells) and the other overexpressing GlKMT2 (glkmt2-ha transgenic cells). We found that the glktm2-as transgenic cells showed an arrest in progress at the late encystation stage. Consequently, the number of cysts produced was lower than that of the control cells. On the other hand, we found that the overexpression of GlKMT2 acts as a negative mutant of the enzyme. In this way, these glktm2-ha transgenic cells showed the same behavior during growth and encystation as glkmt2-as transgenic cells. This interplay between different enzymes acting during encystation reveals the complex process behind the differentiation of the parasite. Understanding how these enzymes play their role during the encystation of the parasite would allow the design of inhibitors to control the parasite.
    Keywords:  Giardia lamblia; cysts; epigenetics; lysine methyltransferase 2; methylation
    DOI:  https://doi.org/10.1016/j.actatropica.2024.107295
  23. Biomed Pharmacother. 2024 Jun 20. pii: S0753-3322(24)00866-7. [Epub ahead of print]177 116982
    Advances in the interaction of glycolytic reprogramming with lactylation.
    Yue Li, Qian Cao, Yibao Hu, Bisha He, Ting Cao, Yun Tang, Xiang Ping Zhou, Xiao Peng Lan, Shuang Quan Liu.
      Lactylation is a novel post-translational modification (PTM) involving proteins that is induced by lactate accumulation. Histone lysine lactylation alters chromatin spatial configuration, influencing gene transcription and regulating the expression of associated genes. This modification plays a crucial role as an epigenetic regulatory factor in the progression of various diseases. Glycolytic reprogramming is one of the most extensively studied forms of metabolic reprogramming, recognized as a key hallmark of cancer cells. It is characterized by an increase in glycolysis and the inhibition of the tricarboxylic acid (TCA) cycle, accompanied by significant lactate production and accumulation. The two processes are closely linked by lactate, which interacts in various physiological and pathological processes. On the one hand, lactylation levels generally correlate positively with the extent of glycolytic reprogramming, being directly influenced by the lactate concentration produced during glycolytic reprogramming. On the other hand, lactylation can also regulate glycolytic pathways by affecting the transcription and structural functions of essential glycolytic enzymes. This review comprehensively outlines the mechanisms of lactylation and glycolytic reprogramming and their interactions in tumor progression, immunity, and inflammation, with the aim of elucidating the relationship between glycolytic reprogramming and lactylation.
    Keywords:  Epigenetics; Glycolytic reprogramming; Lactate; Lactylation; Post-translational modifications; Warburg effect
    DOI:  https://doi.org/10.1016/j.biopha.2024.116982
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