bims-toxgon 2025-04-13 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–04–13
seven papers selected by
Lakesh Kumar, BITS Pilani

Highlights of Toxoplasma gondii research papers published in Parasitology in the last 5 decades: personal perspective.
An ISWI-related chromatin remodeller regulates stage-specific gene expression in Toxoplasma gondii.
HOPS/CORVET tethering complexes are critical for endocytosis and protein trafficking to invasion related organelles in malaria parasites.
Designing a multi-epitope vaccine using Toxoplasma ROP5, ROP7, and SAG1 epitopes and immunogenicity evaluation against acute and chronic toxoplasmosis in BABL/c mice.
Epigenetics and Mitochondrial Biogenesis: The Role of Sirtuins in HIV Neuropathogenesis.
Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.
OsHDAC1 deacetylates the aldehyde dehydrogenase OsALDH2B1, repressing OsGR3 and decreasing salt tolerance in rice.

Parasitology. 2025 Apr 11. 1-8

Highlights of Toxoplasma gondii research papers published in Parasitology in the last 5 decades: personal perspective.

Jitender P Dubey.



Keywords:  abortion; behaviour; chemotherapy; congenital; diagnosis; epidemiology; molecular; toxoplasma gondii; transmission; vaccine

DOI:  https://doi.org/10.1017/S0031182025000186
Nat Microbiol. 2025 Apr 11.

An ISWI-related chromatin remodeller regulates stage-specific gene expression in Toxoplasma gondii.

Belen Pachano, Dayana C Farhat, Martina Shahinas, Jill von Velsen, Charlotte Corrao, Lucid Belmudes, Pieter-Jan de Bock, Caroline Mas, Yohann Couté, Matthew W Bowler, Alexandre Bougdour, Christopher Swale, Mohamed-Ali Hakimi.

ATP-dependent chromatin remodellers are specialized multiprotein machines that organize the genome in eukaryotic cells and regulate its accessibility by repositioning, ejecting or modifying nucleosomes. However, their role in Toxoplasma gondii is poorly understood. Here we show that T. gondii has evolved two divergent proteins within the imitation switch (ISWI) family: TgSNF2h and TgSNF2L. TgSNF2h specifically forms a core complex with the transcription factor AP2VIII-2 and the scaffold protein TgRFTS. Depletion of TgRFTS phenocopies the knockdown of TgSNF2h, restricting access to chromatin and altering local gene expression. At the genomic level, TgSNF2h insulates highly transcribed genes from silenced neighbours, ensuring stage-specific gene regulation. By modulating chromatin accessibility to transcription factors, TgSNF2h exerts epistatic control over MORC, a key regulator of sexual commitment. Our findings show that a specific ISWI complex orchestrates the partitioning of developmental genes and ensures transcriptional fidelity throughout the parasite life cycle.

DOI: https://doi.org/10.1038/s41564-025-01980-2
PLoS Pathog. 2025 Apr 08. 21(4): e1013053

HOPS/CORVET tethering complexes are critical for endocytosis and protein trafficking to invasion related organelles in malaria parasites.

Joëlle Paolo Mesén-Ramírez, Gwendolin Fuchs, Jonas Burmester, Guilherme B Farias, Ana María Alape-Flores, Shamit Singla, Arne Alder, José Cubillán-Marín, Carolina Castro-Peña, Sarah Lemcke, Holger Sondermann, Mónica Prado, Tobias Spielmann, Danny Wilson, Tim-Wolf Gilberger.

The tethering complexes HOPS/CORVET are central for vesicular fusion through the eukaryotic endolysosomal system, but the functions of these complexes in the intracellular development of malaria parasites are still unknown. Here we show that the HOPS/CORVET core subunits are critical for the intracellular proliferation of the malaria parasite Plasmodium falciparum. We demonstrate that HOPS/CORVET are required for parasite endocytosis and host cell cytosol uptake, as early functional depletion of the complex led to developmental arrest and accumulation of endosomes that failed to fuse to the digestive vacuole membrane. Late depletion of the core HOPS/CORVET subunits led to a severe defect in merozoite invasion as a result of the mistargeting of proteins destined to the apical secretory organelles, the rhoptries and micronemes. Ultrastructure-expansion microscopy revealed a reduced rhoptry volume and the accumulation of numerous vesicles in HOPS/CORVET deficient schizonts, further supporting a role of HOPS/CORVET in post-Golgi protein cargo trafficking to the invasion related organelles. Hence, malaria parasites have repurposed HOPS/CORVET to perform dual functions across the intraerythrocytic cycle, consistent with a canonical endocytic pathway for delivery of host cell material to the digestive vacuole in trophozoite stages and a parasite specific role in trafficking of protein cargo to the apical organelles required for invasion in schizont stages.

DOI: https://doi.org/10.1371/journal.ppat.1013053
Microb Pathog. 2025 Apr 09. pii: S0882-4010(25)00292-X. [Epub ahead of print] 107567

Designing a multi-epitope vaccine using Toxoplasma ROP5, ROP7, and SAG1 epitopes and immunogenicity evaluation against acute and chronic toxoplasmosis in BABL/c mice.

Zeinab Moghadamizad, Abdolhossein Dalimi, Majid Pirestani, Fatemeh Ghafarifar.

  This study designed and evaluated a multi-epitope DNA vaccine targeting Toxoplasma gondii immunodominant antigens-ROP5, ROP7, and SAG1-to assess its protective efficacy against acute and chronic toxoplasmosis in BALB/c mice. A bioengineered multi-epitope vaccine construct (MEVC) was synthesized by integrating computationally predicted B- and T-cell epitopes using SAPGTP linkers to ensure conformational stability and epitope accessibility. In silico analyses confirmed the MEVC's antigenicity (VaxiJen score: 0.96), non-allergenicity, solubility (GRAVY index: -0.45), and physicochemical stability (instability index: 32.14; aliphatic index: 78.3), supporting its suitability for immunization. The codon-optimized sequence (753 bp; 253 amino acids) was cloned into the pcDNA3.1(+) plasmid and amplified in Escherichia coli TOP10 cells. Thirty-six female BALB/c mice (6-8 weeks) were divided into three groups (n=12/group) and immunized intramuscularly with 100 μg MEVC, empty vector, or phosphate-buffered saline (PBS) at weeks 0, 2, and 4. Post-immunization, mice were challenged with acute (2×103 RH strain tachyzoites, intraperitoneal) or chronic (10 PRU strain cysts, oral) infection. Molecular docking simulations demonstrated high-affinity binding of the MEVC to murine toll-like receptor 4 via hydrogen bonds and hydrophobic interactions, suggesting adjuvant-like immunogenicity. In vitro expression in HEK-293 cells confirmed protein synthesis, with Western blot detecting a 26 kDa immunoreactive band. MEVC-immunized mice exhibited significantly elevated anti-Toxoplasma IgG titers (1:12,800), dominated by IgG2a isotypes (P < 0.05), and robust IFN-γ production, indicative of Th1-polarized immunity. IL-4 levels remained low, confirming minimal Th2 skewing. Vaccination reduced cerebral cyst burden by 76% (P < 0.01) in chronic infection, yet survival post-acute challenge extended only two days compared to controls. These results demonstrate partial protection against toxoplasmosis, with the MEVC eliciting cellular and humoral responses effective against chronic infection but limited efficacy in acute settings.

Keywords:  BALB/c mice; DNA vaccine; Immunoinformatics; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.micpath.2025.107567
Mol Neurobiol. 2025 Apr 08.

Epigenetics and Mitochondrial Biogenesis: The Role of Sirtuins in HIV Neuropathogenesis.

James Haorah, Hemavathi Iyappan, Malaroviyam Samikkannu, Karthick Chennakesavan, Jay P McLaughlin, Thangavel Samikkannu.

  Mitochondrial energy deficits play a central role in HIV-associated neurocognitive disorder (HAND). HIV disrupts cellular functions, including epigenetic modifications such as class III histone deacetylation mediated by sirtuins (SIRTs). However, the role of SIRTs in HAND pathogenesis remains unclear. We hypothesize that HIV alters mitochondrial biogenesis and energy homeostasis by modifying SIRT family members 1-7, contributing to HAND progression. To test this hypothesis, we examined postmortem frontal lobe brain tissue from people with HIV (PWH) and HIV-negative controls, focusing on epigenetic alterations in SIRTs 1-7, the energy sensor adenosine monophosphate-activated protein kinase (AMPK), the mitochondrial master regulator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and transcription factors such as mitochondrial transcription factor A (TFAM), nuclear respiratory factors 1 and 2 (NRF-1/2), and factors associated with oxidative phosphorylation (OXPHOS). Our analysis revealed a significant increase in AMPK, OXPHOS, and PGC-1α levels, alongside a decrease in TFAM levels in PWH brains compared to uninfected controls. NRF-1 was upregulated in mitochondria but downregulated in the cytoplasm, while NRF-2 exhibited the opposite trend in PWH compared to HIV-negative controls. The epigenetic signatures of SIRTs 1, 2, 3, 4, 6, and 7 were upregulated in PWH, while SIRT5 was downregulated compared to uninfected brain tissues. We exposed primary human astrocyte and microglial cultures to the HIV-1 transactivator of transcription (Tat) protein to identify the cell types involved. These studies confirmed that HIV-induced epigenetic modifications of SIRTs and mitochondrial impairments occurred in both astrocytes and microglia, highlighting the crucial role of SIRTs in HAND pathogenesis.

Keywords:  Epigenetic modification; HAND; HIV; Mitochondrial biogenesis; Sirtuins

DOI:  https://doi.org/10.1007/s12035-025-04885-7
Cell Oncol (Dordr). 2025 Apr 07.

Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.

Chaoqun Li, Cun Ge, Qingwen Wang, Peng Teng, Heyuan Jia, Surui Yao, Zhaohui Huang.

   PURPOSE: Post-translational modifications, such as lactylation, are emerging as critical regulators of metabolic enzymes in cancer progression. Mitochondrial malic enzyme 2 (ME2), a key enzyme in the TCA cycle, plays a pivotal role in maintaining redox homeostasis and supporting tumor metabolism. However, the functional significance of ME2 lactylation and its regulatory mechanisms remain unclear. This study investigates the role of ME2 K352 lactylation in modulating enzymatic activity, redox balance, and tumor progression.
METHODS: Immunoprecipitation and western blotting were used to assess ME2 lactylation and its interaction with Sirtuin 3 (SIRT3). Mass spectrometry identified the lactylation site on ME2. Enzymatic activity was measured using NADH production assays. The functional effects of ME2 K352 lactylation were analyzed by measuring ROS levels, NADP⁺/NADPH ratios, metabolic intermediates, and mitochondrial respiration parameters. Cell proliferation was evaluated via CCK-8 and colony formation assays. Xenograft tumor models and Ki-67 immunohistochemical staining were used to assess tumor growth and proliferation in vivo.
RESULTS: Mass spectrometry identified K352 as the primary lactylation site on ME2. Sodium lactate treatment enhanced ME2 lactylation and enzymatic activity, while SIRT3-mediated delactylation at K352 reduced ME2 activity, disrupting redox homeostasis. Cells expressing the K352R mutant exhibited elevated ROS levels, higher NADP⁺/NADPH ratios, and altered levels of metabolic intermediates, including increased malate and lactate with reduced pyruvate. Additionally, re-expression of ME2 K352R in HCT116 cells significantly impaired proliferation and colony formation. In vivo, xenograft models demonstrated that ME2 K352R expression suppressed tumor growth, as evidenced by reduced tumor volume, weight, and Ki-67 staining.
CONCLUSIONS: This study reveals that ME2 K352 lactylation is a critical regulatory mechanism that modulates enzymatic activity, mitochondrial function, and tumor progression. SIRT3-mediated delactylation of ME2 K352 disrupts redox homeostasis and inhibits tumor growth. These findings highlight the potential of targeting ME2 lactylation as a therapeutic strategy in cancer treatment.

Keywords:  Cancer metabolism; Lactylation; ME2; Mitochondrion; Posttranslational modification; SIRT3

DOI:  https://doi.org/10.1007/s13402-025-01058-5
Plant Physiol. 2025 Apr 11. pii: kiaf149. [Epub ahead of print]

OsHDAC1 deacetylates the aldehyde dehydrogenase OsALDH2B1, repressing OsGR3 and decreasing salt tolerance in rice.

Yequn Wu, Jiaqi Hou, Huangzhuo Xiao, Shiqi Ye, Daoyi Tu, Ronghua Qiu, Xiaoci Ma, Yating Zhao, Tingyu Chen, Lijia Li.

  Salt stress poses a significant challenge to the growth and productivity of rice (Oryza sativa L.). Histone deacetylases (HDACs) play a vital role in modulating responses to various abiotic stresses. However, how OsHDAC1 responds to salt stress remains largely unknown. Here, we report that OsHDAC1 decreases salt tolerance in rice through post-translational modification of metabolic enzymes. Specifically, the rice OsHDAC1 RNAi lines exhibited enhanced resilience to salt stress, while plants overexpressing OsHDAC1 were notably more sensitive. OsHDAC1 interacts with the aldehyde dehydrogenase (ALDH) OsALDH2B1 and deacetylates it at K311 and K531, triggering ubiquitin-proteasome-mediated degradation of OsALDH2B1. OsALDH2B1 can directly target OsGR3, which encodes a type of glutathione reductase critical for reactive oxygen species (ROS) scavenging. Compared with wild-type plants, OsALDH2B1-overexpressing plants exhibited higher OsGR3 expression levels and increased salt resistance, whereas OsALDH2B1 RNAi lines showed reduced OsGR3 expression and lower salt resistance. Collectively, our data suggest that salt stress down-regulates OsHDAC1, resulting in an increase in the acetylation level of OsALDH2B1, which in turn stabilizes OsALDH2B1 and promotes its activity in the regulation of OsGR3 transcription. This OsHDAC1/OsALDH2B1/OsGR3 regulatory module represents an alternative pathway for governing salt stress adaptation in rice.

Keywords:  OsALDH2B1; OsGR3; OsHDAC1; rice; salt stress

DOI:  https://doi.org/10.1093/plphys/kiaf149