bims-toxgon 2026-07-12 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2026–07–12
twelve papers selected by
Lakesh Kumar, BITS Pilani

Progesterone interferes with microtubule-dependent cell division in Toxoplasma gondii.
Yeast Rpd3L histone deacetylase couples nutrient shifts to genome-wide chromatin reprogramming.
Targeting the cGAS-STING pathway alleviates neuroinflammation and cognitive impairment induced by chronic infection of Toxoplasma gondii.
Protein kinase G regulates microneme exocytosis through a microneme-localized ion transport domain-containing protein in Neospora caninum.
In Vivo Quantification of Histone Acetylation Turnover and Acetyl-CoA Sources Using ²H₂O Metabolic Labeling and High-Resolution Mass Spectrometry.
Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
A metabolite-bridged complex between SerRS and SIRT2 couples NAD⁺ metabolism to translation control.
Cell cycle checkpoint activity in the malaria parasite Plasmodium falciparum.
HDAC5 depletion promotes hyper-acetylation of FOXA1 and potentiates HIF1α transcriptional activation in pancreatic cancer.
Dynamic control of nucleotide metabolism in physiology and disease.
Development of Indole-3-yl-methylene-thiobarbital Derivatives as Inhibitors of HDAC8 Enzyme Activity.
Molecular Architecture and Energy Visualization: Advancing Insights into Protein Structure, Interactions, and Activity.

Parasit Vectors. 2026 Jul 09.

Progesterone interferes with microtubule-dependent cell division in Toxoplasma gondii.

Zhili Shan, Zifu Zhu, Na Yang, Yanqun Pei, Jing Liu, Yong Fu, Qun Liu.

   BACKGROUND: Toxoplasma gondii is an opportunistic intracellular parasite that can cause severe reproductive disorders during pregnancy. Progesterone is markedly elevated during pregnancy and has been shown to affect the replication of T. gondii. However, the downstream cellular processes and molecular mechanisms underlying progesterone-mediated regulation of parasite replication remain unclear.
METHODS: Transcriptomic analysis was performed to investigate the global gene expression changes in tachyzoites after progesterone treatment. Differentially expressed genes were subjected to functional enrichment analysis. The effects of progesterone on parasite division were further assessed by immunofluorescence assays targeting subpellicular microtubules, centrosome, and organelles.
RESULTS: Transcriptomic analysis identified 329 differentially expressed genes after progesterone treatment, which were mainly enriched in microtubule-associated pathways, including microtubule motor activity and microtubule-based movement. Although the overall structure of subpellicular microtubules showed no detectable alteration, progesterone selectively disrupted division of the outer core of the centrosome, while the inner core of the centrosome was largely unaffected. Further analysis of organelle division showed that progesterone mainly interfered with early events of endodyogeny, including the segregation of the centrosome, Golgi, and apicoplast, whereas later division-related structures were less affected.
CONCLUSIONS: These findings indicate that progesterone impairs T. gondii replication by selectively interfering with microtubule-dependent processes, especially outer core centrosome division. This study provides new insight into how the pregnancy-associated hormone progesterone regulates parasite replication.

Keywords:   Toxoplasma gondii ; Centrosome division; Microtubule-associated pathways; Progesterone

DOI:  https://doi.org/10.1186/s13071-026-07442-w
Cell Rep. 2026 Jul 08. pii: S2211-1247(26)00729-1. [Epub ahead of print]45(7): 117651

Yeast Rpd3L histone deacetylase couples nutrient shifts to genome-wide chromatin reprogramming.

Saikat Bhattacharya, Benjamin M Sutter, Benjamin P Tu.

  Adaptive transcriptional rewiring underlies the metabolic flexibility of Saccharomyces cerevisiae. We demonstrate that the histone deacetylase Rpd3 mediates nutrient-dependent chromatin reprogramming that coordinates transcriptional shutdown and global acetylation balance during metabolic transitions. Genome-wide analyses reveal that Rpd3 complexes drive rapid, reversible histone deacetylation across promoters and gene bodies, fine-tuning transcriptional output. Rpd3, primarily through the large complex (Rpd3L), localizes at promoters of active genes enriched in H3K9ac and the acetyltransferase Gcn5. Upon nutrient shift, Gcn5 disengages while Rpd3-mediated H3K9 deacetylation enforces repression. Loss of Rpd3 or its Rpd3L-specific subunit, Pho23, disrupts this balance, resulting in the aberrant persistence of growth programs upon starvation and defective activation of respiratory genes in the presence of glucose. HDACs thus can act as metabolic gatekeepers, coupling nutrient cues to chromatin reprogramming and ensuring transcriptional fidelity during metabolic transitions, thereby resolving the long-standing paradox of HDAC enrichment at active promoters.

Keywords:  CP: molecular biology; HDAC; Rpd3; deacetylation; epigenetics; histone acetylation; metabolism; yeast

DOI:  https://doi.org/10.1016/j.celrep.2026.117651
J Neuroinflammation. 2026 Jul 04.

Targeting the cGAS-STING pathway alleviates neuroinflammation and cognitive impairment induced by chronic infection of Toxoplasma gondii.

Yihui Xing, Huiling Lv, Peixuan He, Yongyao Xu, Weifan Shen, Ziyan Gu, Fan Zeng, Yifan Zhang, Kai Sui, Yurui Shi, Yinghua Yu, Wei Pan, Cheng He.

  Chronic infection of Toxoplasma gondii has been established as a contributor to cognitive impairment via inducing sustained neuroinflammation and synaptic damage. However, the underlying mechanisms remain poorly understood. As a key regulator of both neuroinflammation and cellular senescence, Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is implicated in pathogenesis induced by T. gondii infection. Here, we found that cGAS-STING pathway was activated in the cerebral cortex of mouse chronically infected with T. gondii, as indicated by the elevated protein levels of cGAS and STING, and increased phosphorylation of TBK1 and IRF3. Pharmacological inhibition of this pathway with RU.521 and H151, specific inhibitors of cGAS and STING, significantly alleviated T. gondii-induced cognitive impairment and neuronal damage. Moreover, chronic T. gondii infection was shown to trigger senescence characterized by increased expression of senescence markers P16, P21 and P53, and senescence-associated secretory phenotypes (SASPs), including Il-1β, Il-6, Tnf-α, Cxcl1, Cxcl10 and Mmp9. In addition, elevated expression of β-galactosidase, a senescence marker, was predominantly observed in neurons compared to microglia and astrocytes, indicating a primary role for neurons in infection-associated senescence. Notably, these phenotypes of senescence were rescued by inhibition of the cGAS-STING pathway. Collectively, our findings demonstrate that chronic infection of T. gondii activates the cGAS-STING pathway, which in turn drives neuroinflammation and cognitive dysfunction in which neuronal senescence plays a contributory role. Targeting this pathway alleviates T. gondii-induced cognitive decline, highlighting its therapeutic potential against infection-triggered neurodegenerative diseases.

Keywords:   Toxoplasma gondii ; cGAS-STING; cellular senescence; cognitive impairment

DOI:  https://doi.org/10.1186/s12974-026-03937-6
Int J Parasitol. 2026 Jul 09. pii: S0020-7519(26)00155-4. [Epub ahead of print] 104924

Protein kinase G regulates microneme exocytosis through a microneme-localized ion transport domain-containing protein in Neospora caninum.

Xianmei Wang, Na Yang, Shui Yu, Kun Guo, Shiman Yang, Lifang Wang, Qun Liu, Yong Fu, Jing Liu.

  Neospora caninum is a major apicomplexan pathogen causing bovine abortion, resulting in major economic losses to the global livestock industry. Since its initial identification in 1988, N. caninum has emerged as one of the leading infectious causes of bovine abortion worldwide. Protein kinase G (PKG) acts as a central regulator of parasite motility, invasion, and egress; however, the downstream effectors that mediate these processes remain poorly defined. To systematically define the PKG-associated signaling network, we employed TurboID-mediated proximity labeling combined with subcellular localization profiling and phosphoproteomic analysis, identifying 37 high-confidence candidate proteins associated with PKG. These proteins are involved in vesicular trafficking, ion transport and metabolism, transcriptional regulation, and phosphoinositide/cyclic nucleotide signaling. We further identified a previously uncharacterized microneme-localized protein containing ion-transport domains, ITP1, that shows proximity to PKG and exhibits PKG-dependent phosphorylation. Genetic ablation of ITP1 significantly impaired parasite invasion and egress and reduced microneme protein secretion. These findings support a functional link between PKG signaling and ion transport-associated processes in the regulation of microneme exocytosis and host cell invasion in apicomplexan parasites.

Keywords:  Neospora caninum; host cell invasion; ion transport; microneme secretion; protein kinase G

DOI:  https://doi.org/10.1016/j.ijpara.2026.104924
bioRxiv. 2026 Jun 29. pii: 2026.06.26.734905. [Epub ahead of print]

In Vivo Quantification of Histone Acetylation Turnover and Acetyl-CoA Sources Using ²H₂O Metabolic Labeling and High-Resolution Mass Spectrometry.

Andrea Arias-Alvarado, Usman Sabir, Serguei Ilchenko, Spencer Parrish, Mirjavid Aghayev, Wentao He, Tsung-Heng Tsai, Guo-Fang Zhang, Takhar Kasumov.

Dysregulated histone acetylation links cellular metabolism to gene expression, but measuring its in vivo turnover remains technically challenging. Here, we introduce a 2 H2O -based metabolic labeling method coupled with high-resolution Orbitrap mass spectrometry to quantify in vivo histone acetylation dynamics. The approach leverages differing deuterium incorporation rates between fast-labeling acetyl groups and slow-labeling peptide backbones. A two-tier analytical workflow uses full-scan mass spectrometry for mono-acetylated peptides, combined with parallel reaction monitoring (PRM) to resolve site-specific turnover and stoichiometry. Furthermore, monitoring acetyl-group plateau 2 H enrichment enables the evaluation of specific substrate contributions to the acetyl-CoA pool supporting histone acetylation. To demonstrate biological utility, we applied this approach to mice maintained on a high-carbohydrate diet or subjected to 48-h fasting to assess nutrient-dependent histone acetylation dynamics. Acetyl-group labeling reflected the metabolic origin of acetyl-CoA, showing greater 2 H enrichment in the fed state and reduced enrichment during fasting due to increased utilization of unlabeled fatty acid-derived acetyl-CoA. Fasting accelerated acetylation turnover across multiple histone sites and reduced overall acetylation stoichiometry. Quantitative tracing revealed that fatty acid oxidation becomes an important contributor to histone acetylation during fasting, whereas glucose remains the predominant source of nucleo-cytosolic acetyl-CoA (supplying > 60% of acetylation used carbon). This approach enables simultaneous in vivo assessment of histone acetylation turnover, site occupancy, and acetyl-CoA substrate utilization, offering a robust platform to investigate metabolic-epigenetic crosstalk in health and disease.

DOI: https://doi.org/10.64898/2026.06.26.734905
Elife. 2026 07 08. pii: RP107953. [Epub ahead of print]14

Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.

Joy Omini, Inga Krassovskaya, Taiwo Adeolu Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.

  The tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase (MDH1) and citrate synthase (CIT1) form a multienzyme complex, referred to as a metabolon, that channels intermediate oxaloacetate between their reaction centers. Given that the MDH1-CIT1 metabolon enhances pathway reactions in vitro, its dynamic assembly is hypothesized to contribute to TCA cycle regulation in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the respiratory activity was enhanced by acetate. Pharmacological TCA cycle inhibition dissociated the complex, whereas electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially, variations in buffer pH within the physiological pH range between 6.0 and 7.0 in the mitochondrial matrix significantly impacted the MDH1-CIT1 affinity. These results demonstrate the dynamic association and dissociation of the MDH1-CIT1 metabolon and its relationship with respiratory activity, supporting metabolon dynamics as an integral factor in metabolic regulation governed by multiple factors such as mitochondrial pH and metabolite levels.

Keywords:  S. cerevisiae; biochemistry; chemical biology; citrate synthase; malate dehydrogenase; metabolon; mitochondria; oxidative respiration; tricarboxylic acid cycle

DOI:  https://doi.org/10.7554/eLife.107953
Nat Commun. 2026 Jul 08.

A metabolite-bridged complex between SerRS and SIRT2 couples NAD⁺ metabolism to translation control.

Qian Zhang, Huimin Zhang, Marscha Hirschi, Sheng Li, Gabriel C Lander, Jie Yang, Xiang-Lei Yang.

Cellular homeostasis requires tight coordination between metabolic and translational networks. Here we identify a direct molecular link between these processes through a cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) in complex with the NAD⁺-dependent deacetylase SIRT2. This interaction is promoted by the NAD⁺ metabolite ADP-ribose (ADPR), which acts as a molecular bridge between the two enzymes. Within the SIRT2 active site, ADPR engages SerRS residue K414 located in a flexible catalytic-domain loop. Acetylation of K414 is dispensable for binding. Functionally, complex formation inhibits SIRT2 deacetylase activity by blocking substrate access, while SIRT2 association suppresses SerRS aminoacylation activity by preventing tRNA binding. Thus, SerRS and SIRT2 mutually regulate each other, with ADPR enhancing while tRNA attenuating their interaction. Oxidative stress promotes this interaction via a PARP1-dependent pathway, revealing an ADPR-responsive regulatory module that couples metabolic state to translational output. This regulatory module is likely conserved across vertebrates.

DOI: https://doi.org/10.1038/s41467-026-75266-4
mSphere. 2026 Jul 10. e0034126

Cell cycle checkpoint activity in the malaria parasite Plasmodium falciparum.

Monique K Johnson, Juliana Naldoni, William H Lewis, Ross F Waller, Catherine J Merrick.

  Plasmodium spp. have different modes of cell division from most eukaryotes. Little is known about how these are controlled, and cell cycle checkpoints are particularly poorly characterized. However, parasites can arrest their cell cycle when treated with the frontline antimalarial drug artemisinin, and artemisinin-resistant parasites can modulate their cell cycle progression, so it is important to understand these aspects of Plasmodium biology. Here, we show that P. falciparum displays hallmarks of an intra-S-phase checkpoint when exposed to DNA damage, including acute reduction of DNA replication and phosphorylation of a putative damage-marker histone. Compounds that inhibit human checkpoint kinases can inhibit this arrest of DNA replication and synergize with DNA damage in parasite killing. This suggests the existence of checkpoint kinase activity in P. falciparum, yet these kinases have no clear homologues in Plasmodium genomes. Their closest homologs are the phosphatidylinositol lipid kinases. We hypothesize that phosphatidylinositol 3-kinase-which is reportedly upregulated in artemisinin-resistant parasites-may moonlight in this role, and we characterize this essential kinase for the first time via expansion microscopy. Finally, we show that the cryptic checkpoint-kinase activity may also regulate the ring-stage survival phenotype after artemisinin damage, which resembles a G1/S checkpoint. Hence, we suggest that checkpoint kinase inhibitors are candidates for synergy with artemisinin.IMPORTANCEMalaria parasites infect red blood cells, wherein they replicate to produce many new parasites. This is unusual because most cells replicate simply by copying their genome and splitting in half (called binary fission), but malaria parasites make ~20 genome copies and then partition them simultaneously into 20 new cells (called schizogony). Here, we studied how schizogony is controlled: in particular, are there "checkpoints," i.e., pathways that can pause the cell cycle? We found that DNA damage did cause checkpoint hallmarks, yet the key proteins that enforce this in other cells are absent in malaria parasites. Furthermore, this checkpoint activity may be involved in the response to an antimalarial drug, in which parasites pause their cycle before active replication begins. This implies that inhibiting the checkpoint could exacerbate parasite killing by such drugs. Cancer therapies often work like this-by damaging DNA and also preventing the cancer cells from repairing it.

Keywords:  Malaria; PI3K; Plasmodium; cell cycle; checkpoint

DOI:  https://doi.org/10.1128/msphere.00341-26
Mol Cell. 2026 Jul 07. pii: S1097-2765(26)00411-9. [Epub ahead of print]

HDAC5 depletion promotes hyper-acetylation of FOXA1 and potentiates HIF1α transcriptional activation in pancreatic cancer.

Gengdu Qin, Haixin Yu, Yuhan Zhao, Wentao Xia, Yang Qin, Xueyi Liang, Taoyu Chen, Yuxuan Li, Tianhao Zou, Jiaying Liu, Junpeng Meng, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Tao Yin, Shanmiao Gou, Heshui Wu, Xin Jin, Yingke Zhou.

  The biological significance of forkhead box A1 (FOXA1) in non-steroid-driven malignancies, such as pancreatic ductal adenocarcinoma (PDAC), has garnered increasing recognition. It assumes a pivotal role in regulating critical processes such as PDAC cell lineage, metabolism, and metastasis. However, its regulatory mechanisms remain elusive. Here, we demonstrate that histone deacetylase 5 (HDAC5) mediates the deacetylation of FOXA1 at lysine residue 270 (K270), leading to repression of FOXA1's global chromatin occupancy. In HDAC5-loss PDAC, K270 hyper-acetylated FOXA1 is reprogrammed to the transcription start sites (TSSs) of HIF1α-targeted genes, functioning as a pioneer factor of HIF1α signaling. Additionally, we show that HDAC5 antagonizes LSD1-mediated FOXA1 activation by converging on the dynamic equilibrium of acetylation-methylation transition at K270. Pharmacological inhibition of HIF1α/LSD1 suppresses the growth and progression of HDAC5-deficient PDAC in in vivo and in vitro models. Our study reveals the role of FOXA1 as a pioneer factor of HIF1α in PDAC, providing potential therapeutic strategies for HDAC5-deficient PDAC.

Keywords:  FOXA1; HDAC5; HIF1α; pancreatic cancer

DOI:  https://doi.org/10.1016/j.molcel.2026.06.022
Nat Cell Biol. 2026 Jul 08.

Dynamic control of nucleotide metabolism in physiology and disease.

Dohun Kim, Gerta Hoxhaj.

Nucleotides are essential for life, serving not only as the building blocks of the genome but also as cellular energy providers, metabolic cofactors and signalling molecules. To sustain cellular function and proliferation, cells must continuously generate, recycle and precisely balance nucleotide pools in response to fluctuating metabolic and environmental demands. Nucleotide metabolism is therefore not a static biosynthetic pathway, but a dynamic system tightly integrated with cell signalling and physiology. Here we highlight the regulatory logic of nucleotide metabolism, from acute post-translational regulation to transcriptional scaling, feedback control and higher-order spatial organization into multi-enzyme assemblies and filaments. Through the lens of human genetic disorders and cancer, we examine how nucleotide depletion, pool imbalance or intermediate toxicity produce striking tissue-selective pathologies. Together, these principles position nucleotide metabolism as a central regulatory axis linking cellular metabolism, signalling and fate in health and disease.

DOI: https://doi.org/10.1038/s41556-026-02004-9
J Med Chem. 2026 Jul 06.

Development of Indole-3-yl-methylene-thiobarbital Derivatives as Inhibitors of HDAC8 Enzyme Activity.

Abdelrahman A F Elsayed, Jianqiu Zhang, Alvan F Shalas, Petra E van der Wouden, Donald J M van Pinxteren, Willem Jespers, Frank J Dekker.

Histone deacetylase 8 (HDAC8), a zinc-dependent class I enzyme, plays key roles in regulating gene expression and is implicated in various malignancies. Although hydroxamic acid-based inhibitors, like PCI-34051, have demonstrated potent HDAC8 inhibition, limitations including poor selectivity, instability, and off-target effects underscore the need for novel scaffolds. Here, we designed and synthesized a series of indole-based (thio)barbiturate derivatives to identify selective HDAC8 inhibitors. Compound 3d showed promising potency (IC50 = 2.9 μM) and selectivity for HDAC8 over other isoforms. Structure-activity relationship studies revealed that thiobarbituric acid and 2-methylindole scaffolds enhanced HDAC8 inhibition. Remarkably, compound 3r emerged as the most potent inhibitor (IC50 = 0.08 μM), exhibiting slow-binding kinetics, nanomolar potency, and high selectivity over HDAC1, 2, 3, and 6. Furthermore, compound 3r selectively induced SMC3 hyperacetylation in THP-1 cells, confirming its functional HDAC8 inhibition. Computational modeling and molecular dynamics simulations rationalized the experimental SAR and suggested an allosteric mechanism of inhibition.

DOI: https://doi.org/10.1021/acs.jmedchem.5c03170
Methods Mol Biol. 2026 ;3043 331-353

Molecular Architecture and Energy Visualization: Advancing Insights into Protein Structure, Interactions, and Activity.

Luis A Landrau Correa, Owen Borden, Oscar Claudio Ares, Arthur D Tinoco.

  Protein biochemistry continues to progress rapidly through ongoing discoveries, from newly identified proteins to fascinating structural insights into mechanisms. Since proteins are the main machinery of cellular life, the desire to visualize their structure, whether through experimental or computationally obtained methods, has greatly increased. The ability to see proteins in three dimensions has become an essential tool in structural biology, protein design, drug development, and related fields. Among the available tools, PyMOL has become one of the most versatile and easy-to-learn platforms for structure visualization, allowing researchers to closely examine proteins and analyze their structural features. This chapter briefly explains how amino acids influence protein structure, then describes the hierarchical levels of protein organization. It illustrates how tertiary and potential quaternary structures form from energy landscapes that direct proper folding. Key regulatory interactions, such as allostery and metal binding, are highlighted. The chapter concludes by discussing PyMOL features for analyzing pH-dependent charge states, solvent accessibility, and structural or sequence alignments to better understand conformational changes and gain deeper structural insights.

Keywords:  Allostery; Protein charge states; Protein electrostatics; Protein energy landscape; Protein sequence and structural alignment; Protein structure; PyMOL; Structure–activity relationship

DOI:  https://doi.org/10.1007/978-1-0716-5320-3_17