bims-toxgon 2026-06-21 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2026–06–21
sixteen papers selected by
Lakesh Kumar, BITS Pilani

Kiss and spit metabolomics highlight the role of host purine metabolism during pathogen infection.
An ER-IMC bridge protein TgVPS13A and an IMC-resident scramblase TgDAT1 drive daughter budding in Toxoplasma gondii.
β-catenin-driven innate and metabolic reprograming in macrophages fuel T-cell-dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention.
Minimum Inoculum of Resistance Assay for Evaluating Antitoxoplasmosis Compounds That Target Phenylalanine tRNA Synthetase.
Vaccination with live-attenuated Toxoplasma gondii mutants RHΔtkl1 and PruΔpp2a-c induces protective immunity in sheep.
Multi-Locus Sequencing for Strain Typing of Toxoplasma gondii.
ENO1 couples HDAC1 to regulate histone lactylation and gene transcription.
Functional Divergence and Structural Changes of class IV Histone Deacetylases (HDACs) Across the Tree of Life.
An Overview of Panobinostat: Pharmacological and Medicinal Chemistry Aspects.
Lysine acetylome profiling reveals a dual regulatory role in carbon flux redirection and RNA degradation inhibition in Mycobacterium smegmatis.
The evolutionary transition from alga to parasite in the sister lineage of apicomplexans.
Chitin deacetylase 3 of Cryptococcus neoformans produces chitosans with low degree and random pattern of acetylation.
From parasite biology to predictive metabolic models.
The metabolic-epigenetic landscape of aging: interplay between histone acetylation, lactylation, and glycation.
The multifaceted role of cAMP signalling in Leishmania pathogenesis and host immune modulation.
ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.

mSphere. 2026 Jun 15. e0025626

Kiss and spit metabolomics highlight the role of host purine metabolism during pathogen infection.

Gina M Gallego-Lopez, William J Olson, Andres M Tibabuzo-Perdomo, David Stevenson, Daniel Amador-Noguez, Grant Lawrence, James W Leahy, Emmanuel Contreras Guzman, Melissa C Skala, Laura J Knoll.

  Intracellular bacteria and protists rely on the host cell to supply many metabolites, but the mechanisms through which pathogens manipulate host metabolism to their benefit are not understood. Here, we demonstrate that when the obligate intracellular parasite Toxoplasma gondii secretes its rhoptry organelle contents into the host cytoplasm before invasion-a process called "kiss and spit"-host cell metabolite abundance is altered in nucleotide synthesis, the pentose phosphate pathway, glycolysis, and amino acid synthesis. U-13C6-labeling metabolomics confirmed that kiss and spit increased the flow of carbon through the pentose phosphate pathway and nucleotide synthesis. An increase in 2,3-bisphosphoglycerate abundance led us to investigate the activation of host cytosolic nucleosidase II (cN-II) to provide purines for the parasite. We found that T. gondii manipulates the host cN-II enzyme to dephosphorylate GMP and IMP that it needs for replication. Furthermore, we found that the approved anti-cancer drug fludarabine, which inhibits cN-II, also inhibits Toxoplasma replication. These results reveal Toxoplasma host cell manipulation and highlight potential therapies for toxoplasmosis.IMPORTANCEA fundamental challenge in parasitology is understanding how intracellular parasites rapidly reprogram host metabolism to support replication. This study reveals that Toxoplasma gondii initiates profound metabolic reprogramming through a "kiss-and-spit" mechanism, secreting effector molecules without invasion. We demonstrate that T. gondii specifically hijacks host cytosolic 5'-nucleotidase II (cN-II) by elevating 2,3-bisphosphoglycerate levels, which allosterically activates this enzyme to generate purines essential for parasite survival. Genetic deletion of host cN-II significantly impairs parasite replication, establishing cN-II as a critical host dependency factor. These findings have important implications for antiparasitic drug development while advancing our understanding of purine metabolism in apicomplexan parasites. More broadly, elucidating the molecular mechanism linking parasite effector secretion to specific host enzyme activation provides a framework for understanding metabolic manipulation across other intracellular pathogens.

Keywords:  Toxoplasma gondii; cN-II enzyme; host–pathogen interaction; metabolomics; purines

DOI:  https://doi.org/10.1128/msphere.00256-26
PLoS Pathog. 2026 Jun 18. 22(6): e1013865

An ER-IMC bridge protein TgVPS13A and an IMC-resident scramblase TgDAT1 drive daughter budding in Toxoplasma gondii.

Lin Zhao, Jiawen Fu, Swaroop Peddiraju, Heming Chen, Keqin Huang, Ying Zhang, Nishith Gupta, Qian Jiang, Honglin Jia.

All alveolates including apicomplexan parasites contain an inner membrane complex (IMC) underneath the plasma membrane. The IMC is synthesized de novo during asexual replication (including endodyogeny, endopolygeny, and schizogony) and serves as a crucial scaffold for supporting cytoskeletal structures and the glideosome machinery for parasite locomotion. However, the mechanism(s) underlying the membrane biogenesis in the IMC are not well understood. Using a clinically-relevant and globally-prevalent pathogenic protist model, Toxoplasma gondii, we identified the TgVPS13A bridging the IMC to the endoplasmic reticulum (ER) - the major site of phospholipid synthesis. The multi-modular TgVPS13A plays a crucial role in the IMC biogenesis, functioning in concert with an ER-resident VAP protein (TgVAP) and a novel lipid scramblase (TgDAT1). TgDAT1 is recruited for the progeny formation sites during the early stages of budding. Conditional depletion of TgVPS13A, TgDAT1 or TgVAP results in collapse of the inner membrane complex, leading to parasite death, as visualized by endodyogeny-specific organelle markers. GFP-Lact-C2, a biosensor of phosphatidylserine and phosphatidylthreonine lipids made in the ER and enriched in the IMC, also mislocalizes upon protein depletion. In conclusion, we propose that TgVPS13A, together with TgVAP and TgDAT1, bridge the ER and IMC and mediate the inter-organelle transport of lipids, thus contributing to the organelle biogenesis and daughter budding in T. gondii.

DOI: https://doi.org/10.1371/journal.ppat.1013865
Cell Death Dis. 2026 Jun 13. pii: 568. [Epub ahead of print]17(1):

β-catenin-driven innate and metabolic reprograming in macrophages fuel T-cell-dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention.

Geetika Kumari, Amit Kumar, Rasmiranjan Muduli, Mayami Das, Prithwik Bhowmik, Biplab Singha, Ankita Namdeo, Criss Dcosta, Neerja Wadhwa, Jaswinder Singh Maras, Rakesh Kundu, Nishith Gupta, Ruchi Anand, Dhanasekaran Shanmugam, Tanmay Majumdar.

Toxoplasma gondii activates innate immunity via TLR11/12 in mice, but the lack of functional human counterparts leaves a gap in understanding parasite sensing in humans. Here, we bridge this gap by uncovering a host-intrinsic sensing mechanism, wherein β-catenin signaling mediates immune recognition of T. gondii. Notably, this parasite hijacks the PI3K-AKT-β-catenin pathway in macrophages to promote its replication. While β-catenin ablation, either genetically or pharmacologically (XAV939), disavows this process, thereby inhibiting replication. Phospho-β-catenin-TCF4 drives IRF4 transcription, followed by phosphorylation of IRF4, which regulates CYBB transcription. Augmented CYBB enhances mitochondrial-ROS and triggers mitophagy via PINK1/PARKIN, whereas ablation of β-catenin preserves mitochondrial fitness, thereby impeding parasite growth. Enhanced ROS can oxidize host mitochondrial DNA, which then functions as a host-associated molecular pattern (HAMP). This activates the cytosolic pathogen recognition receptor (PRR) AIM2, triggering the AIM2-NLRP3-ASC-caspase-1-IL-1β inflammasome cascade. This cascade leads to gasdermin-D-mediated pyroptosis, a process that critically depends on the phosphorylation of β-catenin. T. gondii's ASP5 protease plays an essential role in the phosphorylation of β-catenin-mediated inflammasome activation. Metabolically, β-catenin-dependent enhanced ROS stabilized HIF-1α, which stimulates the HKII-LDH-A axis, promoting the Warburg effect, histone acetylation and pro-inflammatory M1-macrophage polarization (IL-12/IL-6/IL-23/TNF-α). β-catenin ablation shifts metabolism to oxidative-phosphorylation, fostering M2-phenotype (IL-2/IL-10/TGF-β) that abrogates parasites survival. β-catenin also strengthens MHC-TCR avidity, driving Th1/Tc1, Th9/Tc9, and Th17/Tc17 paradigm, whereas β-catenin inhibition promotes anti-inflammatory Th2/Tc2/Threg/Tcreg differentiation. Additionally, macrophage intrinsic β-catenin dictates metabolic divergence in both CD4⁺ and CD8⁺T-cells. Notably, β-catenin-deletion in macrophages protects mice (β-catΔMΦ) against infection, highlighting that XAV939 has therapeutic potential against toxoplasmosis.

DOI: https://doi.org/10.1038/s41419-026-08953-1
ACS Infect Dis. 2026 Jun 18.

Minimum Inoculum of Resistance Assay for Evaluating Antitoxoplasmosis Compounds That Target Phenylalanine tRNA Synthetase.

Taher Uddin, Payal Mittal, Han Xie, Bruno Melillo, Amit Sharma, Arnab K Chatterjee, L David Sibley.

  Toxoplasma gondii is a globally important intracellular parasite, and treatment regimens are limited by the failure of drugs to target latent tissue cysts. Developing new candidates for treatment also needs to address the potential for resistance to arise. Herein, we developed a minimum inoculum for resistance assay as a semiquantitative metric for evaluating inhibitors of T. gondii. The resistance assay, adapted from malaria, measures the frequency of pre-existing resistance alleles by exposing different-sized parasite populations to drug pressure. We profiled a series of bicyclic pyrrolidone analogues that inhibit phenylalanine tRNA synthetase. We demonstrate that these inhibitors require higher inocula to lead to parasite resistance (up to >108 parasites) in comparison with an inhibitor of DNA synthesis and that resistance values vary across inhibitors with closely related chemical structures. Clonal analysis of resistant parasites emerging from resistance assays revealed both new and previously identified resistance-conferring mutations in T. gondii phenylalanine tRNA synthetase, and structural modeling revealed their potential impact on the enzyme active site. The minimum inoculum for resistance assay provides a functional benchmark to compare new and existing inhibitors, allowing for rational prioritization of lead compounds with a high genetic barrier to resistance.

Keywords:  chemotherapy; drug resistance; homology modeling; toxoplasmosis

DOI:  https://doi.org/10.1021/acsinfecdis.6c00221
Parasit Vectors. 2026 Jun 16.

Vaccination with live-attenuated Toxoplasma gondii mutants RHΔtkl1 and PruΔpp2a-c induces protective immunity in sheep.

Ze-Xuan Wu, Yu Kang, Wen-Bo Hao, Yu-Xuan Wang, Zhi Zheng, Shi-Bo Huang, Xiao-Nan Zheng, Xing-Quan Zhu.

   BACKGROUND: Toxoplasma gondii is a globally distributed intracellular parasitic protozoan. It infects nearly all warm-blooded animals and causes a zoonotic disease of worldwide significance. Currently, the only commercially available vaccine, Toxovax®, is solely used for the prevention of Toxoplasma-induced abortion in sheep, but it has limitations such as a short shelf life and the potential of reversion to virulence. This study evaluated the safety and immune-protective efficacy of two live-attenuated strains RHΔtkl1 and PruΔpp2a-c in sheep.
METHODS: Sheep were immunized via intramuscular injection in the neck with 1 × 107 tachyzoites of RHΔtkl1 or PruΔpp2a-c. Sheep were challenged orally with 5 × 105 type II Pru oocysts at 28 days post-vaccination (dpv), followed by a second challenge on day 70 with 1 × 107 type II Pru tachyzoites injected intramuscularly at 70 dpv. Safety and immuno-protection were evaluated by monitoring clinical symptoms and body temperatures, T. gondii-specific IgG antibody levels, histopathological changes, immunohistochemistry, brain cysts, parasite load, and mouse bioassay results.
RESULTS: The results demonstrated that both knockout strains induced only transient fever. Following immunization and subsequent challenge with Pru oocysts, the T. gondii-specific IgG antibody levels in sheep increased rapidly and remained elevated for an extended period. Histopathological analysis indicated mild organ lesions in heart, liver and lung tissues among immunized infected sheep, whereas non-immunized infected sheep exhibited severe widespread inflammation. Immunohistochemical analysis of brain tissue revealed significantly lower values for four parameters (positive cell ratio, density, histochemistry score, immunoreactive score) in immunized groups (P < 0.01). A significant reduction in brain cysts was observed in immunized and challenged sheep (P < 0.01) compared with unimmunized and challenged sheep. The parasite burden of T. gondii in heart tissue was significantly reduced (P < 0.01). Compared with mice inoculated with sheep brain tissue from unimmunized groups challenged with T. gondii Pru oocysts and tachyzoites, mouse bioassay results showed that the mice inoculated with sheep brain tissue from groups immunized with RHΔtkl1 or PruΔpp2a-c tachyzoites and subsequently challenged with T. gondii Pru oocysts and tachyzoites exhibited a significantly lower proportion of positive genomic T. gondii DNA in the brain (P < 0.001), as well as significantly reduced levels of T. gondii-specific antibody IgG in the serum (P < 0.0001). Similarly, mice inoculated with sheep visceral tissue from the same immunized and challenged groups also showed a significantly reduced proportion of positive genomic T. gondii DNA in the brain (P < 0.0001) and significantly reduced levels of T. gondii-specific antibody IgG in the serum (P < 0.0001).
CONCLUSIONS: The gene knockout strains RHΔtkl1 and PruΔpp2a-c showed a certain degree of safety in sheep, and they induced strong humoral and cellular immune responses in sheep, significantly mitigating acute infection symptoms and tissue damage. Notably, PruΔpp2a-c showed greater potential in suppressing cyst formation. Both strains are potential attenuated candidates against sheep toxoplasmosis.

Keywords:   Toxoplasma gondii ; Immunization; Live attenuated vaccine; PruΔpp2a-c ; RHΔtkl1 ; Sheep

DOI:  https://doi.org/10.1186/s13071-026-07516-9
J Vis Exp. 2026 May 26.

Multi-Locus Sequencing for Strain Typing of Toxoplasma gondii.

Abeer A Khedr, Paul W Denny.

Toxoplasma gondii is a globally distributed apicomplexan parasite characterized by substantial genetic diversity, necessitating accurate molecular approaches for strain discrimination. The goal of this protocol is to establish a reproducible workflow for targeted multi-locus genotyping of cultured T. gondii isolates. The procedure involves in vitro propagation of representative Type I (RH) and Type II (ME49) strains, extraction of genomic DNA, locus-specific amplification of the SAG2 and SAG3 genes, and sequencing-based analyses to detect single-nucleotide polymorphisms (SNPs) and insertion/deletion (INDEL) events. Sequencing data are processed to generate high-confidence consensus sequences and to perform comparative alignment for the identification of strain-specific polymorphisms. Application of this workflow to archetypal strains demonstrated high mapping efficiency, consistent read depth across target loci, and accurate recovery of expected amplicon sizes, confirming reliable detection of locus-level genetic variation. Although comprehensive genotype assignment requires inclusion of additional standardized markers, this protocol provides a scalable and reproducible framework for targeted genetic characterization of laboratory-maintained T. gondii isolates and supports consistent multi-locus sequence analysis.

DOI: https://doi.org/10.3791/70645
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2535245123

ENO1 couples HDAC1 to regulate histone lactylation and gene transcription.

Guijin Zhai, Fei Zhao, Yuhan Wang, Zixin Jiang, Yanan Li, Zilong Fan, Wei Zheng, Yanpu Han, Jianji Zhang, Yong Zang, Kai Zhang.

  Histone deacetylases (HDACs) regulate transcription and catalyze deacetylation predominantly within canonical transcriptional complexes. Nevertheless, the mechanistic role of other HDAC-associated proteins in orchestrating this process remains incompletely understood. To systematically decode endogenous HDAC interactomes in living cells, we developed BimPL, a heterobifunctional molecule-enabled proximity labeling strategy. Leveraging BimPL and quantitative proteomics, we robustly captured established HDAC complexes and identified putative interactors, including glycolytic enzyme enolase-1 (ENO1). Importantly, we uncover that ENO1 translocates into the nucleus and interacts with HDAC1 at chromatin, which in turn blunts the activity of HDAC1 through locally generated phosphoenolpyruvate (PEP). Consequently, the ENO1-HDAC1 coupling promotes histone lysine lactylation (Kla), which drives transcriptional reprogramming of oncogenes in hepatic malignancies. Our study establishes BimPL as a versatile tool for mapping endogenous protein interactomes and reveals a metabolic enzyme-orchestrated HDAC regulatory mechanism for histone lactylation, highlighting ENO1's moonlighting function in epigenetic reprogramming.

Keywords:  HDAC interactomes; chemical proteomics; histone lactylation; metabolic reprogramming; proximity labeling

DOI:  https://doi.org/10.1073/pnas.2535245123
Mol Biol Evol. 2026 Jun 17. pii: msag150. [Epub ahead of print]

Functional Divergence and Structural Changes of class IV Histone Deacetylases (HDACs) Across the Tree of Life.

Zora Nováková, Pavla Bartošová-Sojková, Julia Kudláčová, Fady Baselious, Zsófia Kutilová, Pavlína Jaklová, Marat Meleshin, Lucia Motlová, Andrea Schenkmayerova, Vladimír Vrkoslav, Štěpán Strnad, Natan Horáček, Ansgar Gruber, Petr Žáček, Sebastian Kroll, Barbora Havlínová, Markéta Ondráková, Růžena Tučková, Tereza Krunclová, Josef Cvačka, Miroslav Oborník, Mike Schutkowski, Wolfgang Sippl, Cyril Bařinka.

  Class IV histone deacetylases (HDACs) are the least understood branch of the classical zinc-dependent HDAC family with HDAC11 standing out as the sole member of class IV HDACs. Using a broad phylogenetic dataset spanning bacteria, archaea, and eukaryotes, we identified two deeply conserved HDAC11 lineages, clades A and B, that differ in evolutionary origin, predicted subcellular localization, and enzymatic properties. Clade A is enriched in phototrophic eukaryotes and targeted to mitochondria or plastids, whereas clade B predominates in heterotrophs and localizes mainly to the cytoplasm or nucleus. High-resolution crystal structures of selected representatives from each clade revealed a conserved catalytic core but distinct structural features-including electrostatic surface profiles, loop architectures, and foot-pocket geometries-that clearly separate the two lineages and act as sequential "selectivity filters" shaping substrate specificity. Biochemical assays show robust long-chain fatty-acid deacylase activity in clade B enzymes, but no detectable activity for any of clade A representatives against peptide substrates, suggesting adaptation to alternative, non-peptidic targets. Together, these findings define a revised evolutionary framework for HDAC11 and provide structural and functional insights into the diversification of this ancient enzyme family.

Keywords:  evolutionary divergence; fatty-acid deacylase activity; histone deacetylase 11; phylogenetic analysis; structural selectivity filter; substrate profiling

DOI:  https://doi.org/10.1093/molbev/msag150
Chem Biol Drug Des. 2026 Jun;107(6): e70330

An Overview of Panobinostat: Pharmacological and Medicinal Chemistry Aspects.

Ajam C Shaikh, Swastika Banerjee, Vijay Bahadur, Pravin R Bhansali.

  Panobinostat, a potent histone deacetylase inhibitor (HDACi), has been studied for epigenetic control and cancer treatment. It impacts chromatin remodeling, gene transcription, and protein degradation, leading to the progression of the cell cycle and death. This review extensively analyses panobinostat's pharmacological and medicinal chemistry characteristics, including its mode of action, structure-activity relationship, metabolism, synthesis, and repurposing. Current research shows panobinostat to be effective for nononcological indications such as neurological disorders, HIV latency reversal, and fetal haemoglobin reactivation. This review highlights the necessity for continued SAR investigations to improve isoform selectivity and examines the growing clinical applications of panobinostat beyond oncology.

Keywords:  HDACi; anticancer drugs; metabolism; multiple myeloma; panobinostat; repurposing; structure activity relationship; syntheses

DOI:  https://doi.org/10.1111/cbdd.70330
Front Microbiol. 2026 ;17 1823773

Lysine acetylome profiling reveals a dual regulatory role in carbon flux redirection and RNA degradation inhibition in Mycobacterium smegmatis.

Manluan Sun, Qiyu Zhao, Caiquan Zhou, Chenghao Liu, Bingyu Yang, Jia Bu, Ruilan Li, Jiang Bian, Xiaojie Niu, Jinbo Hu, Binyu Liu, Sai Ge.

   Introduction: Mycobacterium tuberculosis in natural environments and host organisms must adapt to constantly changing growth conditions, and its adaptive mechanism for nutrient metabolism represents one response to complex environments. Reversible post-translational protein modifications regulate central metabolic enzymes in M. tuberculosis, thereby governing its adaptation to varying environmental nutrient availability.
Methods: In this study, we cultured Mycobacterium smegmatis MC2155 using Sauton or Middlebrook 7H9 media and applied liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze differences in acetylation-modified proteins. We also performed bioinformatic analysis of the acetylated proteins expressed in the different media.
Results: LC-MS/MS revealed 182 acetylated proteins and 398 sites exclusively in Sauton-medium-cultured strains; whereas 57 acetylated proteins and 141 sites were identified exclusively in nutrient-rich 7H9-medium-cultured strains. Additionally, 302 proteins and 462 sites were differentially acetylated between the Sauton- and 7H9-medium-cultured samples. Our bioinformatics analysis identified differences in whole-protein acetylation modifications in M. smegmatis MC2155 under these two culture conditions, primarily reflected in metabolic pathways, including the citrate cycle (TCA cycle), 2-oxocarboxylic acid metabolism, carbon metabolism, RNA degradation, and tryptophan metabolism.
Discussion: Under the nutrient-limited conditions of Sauton medium culture, multiple sites within isocitrate dehydrogenase exhibited acetylation, leading to reduced enzyme activity. This effect may redirect a greater proportion of carbon flux towards the glyoxylate pathway. Conversely, in 7H9 medium, acetylation at residues K189 and K331 of isocitrate lyase may diminish enzyme activity, thereby channeling increased carbon flux towards the TCA cycle. Acetylation at 3-hydroxyacyl-CoA dehydrogenase (K370) and tryptophan-tRNA synthetase (K200) may reduce fatty acid and protein synthesis, thereby preventing excessive energy expenditure; acetylation at Oligoribonuclease K153 likely diminishes enzyme activity, thereby allowing M. smegmatis to adapt to nutrient limitation by accumulating more c-di-AMP.

Keywords:  7H9 medium; Mycobacterium smegmatis; Sauton medium; lysine acetylation; post-translational modification

DOI:  https://doi.org/10.3389/fmicb.2026.1823773
Curr Biol. 2026 Jun 16. pii: S0960-9822(26)00647-0. [Epub ahead of print]

The evolutionary transition from alga to parasite in the sister lineage of apicomplexans.

Elizabeth C Cooney, Alyssa-Lois Madden Gehman, Patrick J Keeling.

  The chrompodellids are a collection of photosynthetic "chromerids" and heterotrophic "colpodellids," which are together the sister lineage to the apicomplexans,1 a group of parasites containing many human disease-causing agents and species of ecological and economic importance. These lineages all descend from a photosynthetic ancestor and have been a model to understand the evolutionary transition from free-living alga to obligate parasite. Only a handful of species of chrompodellids are described-most are free-living predators, while two are photosynthetic and two are parasitic.1,2,3,4,5 The parasites evolved independently to different forms of parasitism: one is intracellular, and the other is an extracellular gut parasite. Here, we describe a third parasitic chrompodellid, Holdonia amygdala gen. nov. sp. nov., which has an entirely different strategy, being an ectoparasite on the surface of the errantid polychaete, Micropodarke. Using single-cell transcriptomics from four individual cells, phylogenomic analysis of 232 conserved genes shows H. amygdala is not specifically related to either known parasite but instead branches deep within the chrompodellids, which are distantly related to both the intracellular parasite Piridium sociabile and the photosynthetic Vitrella brassicaformis. Despite losing photosynthesis independently, the H. amygdala and P. sociabile plastid genomes have converged on a similar gene content and a non-canonical genetic code. Overall, these data suggest that these are predictable outcomes in the evolutionary transition from free-living alga to heterotrophic parasite that emerge repeatedly in parallel.

Keywords:  apicomplexan; chrompodellid; parasite; plastid; polychaete; single-cell transcriptomics

DOI:  https://doi.org/10.1016/j.cub.2026.05.042
Int J Biol Macromol. 2026 Jun 18. pii: S0141-8130(26)02988-0. [Epub ahead of print]371 153061

Chitin deacetylase 3 of Cryptococcus neoformans produces chitosans with low degree and random pattern of acetylation.

Evelyn Tchoub, Margareta J Hellmann, Bruno M Moerschbacher, Stefan Cord-Landwehr.

  The fungal pathogen Cryptococcus neoformans poses a significant global health concern, accounting for more than 100,000 fatalities among individuals with AIDS alone every year. In contrast to other Basidiomycetes, C. neoformans actively deacetylates the chitin in its cell wall to chitosans. The deacetylation reaction is catalyzed by four chitin deacetylases (CnCDAs 1-4), presumably to evade the chitin-triggered host immunity. In this study, we conducted a comprehensive in vitro characterization of recombinant CnCDA3, revealing a preference for deacetylated units at its -1 subsite, higher activity on longer substrates, and the generation of random acetylation patterns in polymer deacetylation (and N-acetylation) products. In combination with in silico modeling of all CnCDAs, the experimental results suggest that the function of CnCDA3 in vivo may be to further deacetylate cell wall chitosans initially produced from nascent chitin chains by the action of other membrane-associated CnCDAs. Deeper understanding of the actions of these enzymes involved in fungal virulence may facilitate the urgently needed improvement in therapies and the development of effective cell-based vaccines against cryptococcal infections.

Keywords:  Chitin deacetylases; Chitosan; Cryptococcus

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153061
Trends Parasitol. 2026 Jun 13. pii: S1471-4922(26)00151-0. [Epub ahead of print]

From parasite biology to predictive metabolic models.

Lucas Gentil Azevedo, Gabriela Torres Montanaro, Bruno Ribeiro Pinto, Marie-France Sagot, Ariel Mariano Silber, Pablo Ivan Pereira Ramos, Mariana Galvão Ferrarini.

  Protist parasites cause devastating diseases worldwide, yet their complex metabolism remains poorly understood. Genome-scale metabolic models (GEMs) have emerged as powerful tools to systematically represent and simulate parasite metabolism, enabling the prediction of gene essentiality, metabolic vulnerabilities, and host-parasite interactions. This review examines the current landscape of GEMs for protist pathogens, focusing on the key modeling decisions (objective functions, constraints, and compartmentalization) that govern model behavior and predictive scope. We discuss how these choices shape biological interpretability and how inherited assumptions from early reconstructions propagate across successive models. Ongoing challenges in standardization and reusability highlight the need for consistent annotation, validation, and adherence to FAIR data principles to build interoperable and reproducible resources.

Keywords:  constraint-based modeling; genome-scale metabolic models; host–parasite interactions; metabolic networks; protozoan parasites; systems biology

DOI:  https://doi.org/10.1016/j.pt.2026.05.013
Front Aging. 2026 ;7 1854915

The metabolic-epigenetic landscape of aging: interplay between histone acetylation, lactylation, and glycation.

Olena Bolgova, Inna Shypilova, Volodymyr Mavrych.

   Background: The aging epigenome is shaped by three mechanistically distinct histone post-translational modifications-acetylation, lactylation, and glycation-each driven by a different metabolic flux: mitochondrial oxidative phosphorylation, glycolytic lactate production, and reactive carbonyl stress, respectively. Understanding their interplay is central to a molecular physiology of epigenetic aging.
Scope: This mini review synthesizes current evidence on the mechanisms of histone acetylation, lactylation, and glycation in aging; their crosstalk and convergence on shared regulatory nodes; and their modulation by environmental, nutritional, and behavioral factors. Key controversies and research gaps are critically appraised.
Key Findings: NAD + decline in aging disables the sirtuin deacetylase family, dysregulating the histone acetylation landscape and impairing autophagy, mitochondrial biogenesis, and DNA repair. Histone lactylation, written by p300 at H3K18 and related lysine residues, is context-dependent: physiological pulses during exercise and sleep are adaptive, while chronic accumulation in diabetic microglia drives neuroinflammation via TLR4/NF-κB, and excess in tumor cells enables senescence bypass. Histone glycation by methylglyoxal irreversibly displaces regulatory marks and inactivates sirtuin proteins; pharmacological induction of glyoxalase I and glycation-lowering interventions reduce this burden and extend healthspan. These three axes may converge on a unified metabolic-epigenetic collapse that we propose constitutes the cellular basis of an 'aging' metabolic memory.
Controversies and Gaps: Lactylation erasers remain uncharacterized; the pro-versus anti-senescence duality of H3K18la is unresolved; and genome-wide histone glycation mapping in human tissues is absent.
Conclusion: Combinatorial interventions targeting NAD + restoration, modulation of lactylation, and reduction of carbonyl stress offer the most evidence-based approach to slowing metabolic-epigenetic aging.

Keywords:  aging; cellular senescence; epigenetics; histone acetylation; histone glycation; histone lactylation; metabolic memory; methylglyoxal

DOI:  https://doi.org/10.3389/fragi.2026.1854915
Cell Signal. 2026 Jun 15. pii: S0898-6568(26)00337-2. [Epub ahead of print]146 112682

The multifaceted role of cAMP signalling in Leishmania pathogenesis and host immune modulation.

Tapasi Das, Pronay Brahmachari, Pijush K Das, Anindita Ukil.

  Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger involved in regulating numerous cellular processes, including apoptosis, kinase activation, immune responses, and cell cycle progression. In the context of Leishmania infection, emerging evidence highlights how different Leishmania species exploit host and parasite-derived cAMP signalling pathways to modulate host cell functions and promote their survival. This review consolidates current understanding of parasite-mediated modulation of host defence mechanisms through cAMP signalling, thereby emphasising its crucial role in establishing and maintaining a permissive intracellular environment. Furthermore, it elaborates on how cAMP-driven pathways regulate the expression of antioxidant enzymes, inflammatory cytokines and apoptosis, thereby orchestrating immune suppression and facilitating long-term parasite persistence within the host. Moreover, Leishmania further harnesses its endogenous cAMP signalling pathway to drive its differentiation and replication within the host. Understanding these molecular tactics has not only enriched basic science but also opened new avenues for therapeutic interventions. This review underscores the centrality of cAMP signalling in Leishmania pathogenesis and highlights the therapeutic promise of targeting these pathways to develop more effective treatments against leishmaniasis.

Keywords:  Apoptosis; Inflammation; Leishmania; Macrophage; Oxidative stress; cAMP

DOI:  https://doi.org/10.1016/j.cellsig.2026.112682
Nat Commun. 2026 Jun 20.

ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.

Jacklyn M Huhn, Liana Valin, Mary Basse, Judith Sokei, Nishanth Gabriel, Esteban Martinez, Joice S Kanefsky, Stephanie Stransky, Adrienne Dorrance, Ramiro Garzon, Daniela Di Marcantonio, Tomasz Skorski, Aaron R Goldman, Hsin-Yao Tang, Samuele Cortellazzi, Orsola di Martino, John Krais, Simone Sidoli, Francesca Ferraro, David L Wiest, Stephen M Sykes.

Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death. Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity and the differentiation blockade in leukemia cells.

DOI: https://doi.org/10.1038/s41467-026-74324-1