bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2025–10–19
six papers selected by
Lakesh Kumar, BITS Pilani
  1. Function and mechanism of dopamine receptor D2 (DRD2) in neuroinflammation and behavioral disorders in C57BL/6J mice infected with Toxoplasma gondii TgCtWh6 strain.
  2. Tepsin and AP4 mediate transport from the trans-Golgi to the plant-like vacuole in toxoplasma.
  3. NAD+ Homeostasis and Autophagy: Integrated Control Through Nutrient Signaling in Yeast and Mammals.
  4. Tandem Allosteric Effects of Reactant and Product that Promote Deacetylation Cycles in Sir2.
  5. Lysine malonylation as a therapeutic target: implications for metabolic, inflammatory, and oncological disorders.
  6. Epigenetic landscape of Leishmania-host interactions.
  1. Brain Behav Immun. 2025 Oct 15. pii: S0889-1591(25)00378-2. [Epub ahead of print] 106136
    Function and mechanism of dopamine receptor D2 (DRD2) in neuroinflammation and behavioral disorders in C57BL/6J mice infected with Toxoplasma gondii TgCtWh6 strain.
    Hang Sun, Xiaoman Xie, Yanan Li, Wenju Zhu, Yanhan Hou, Huanhuan Xie, Beibei Zhou, Junmei Zhang, Qi Wang, Jinjing Xie, Xin Zhang, Jiao Liu, Hongjie Dong, Guihua Zhao, Chao Xu, Kun Yin.
      Toxoplasma gondii (T. gondii) is a globally distributed protozoan parasite, and its chronic infection has been closely associated with various neuropsychiatric disorders. However, the key susceptibility factors and mechanisms by which T. gondii manipulates host behaviors remain insufficiently understood. In this study, based on the comprehensive behavioral analyses including the AI HomeCage platform, and third-generation Nanopore-seq technology, we demonstrated that the T. gondii strain TgCtwh6 induces depression-like symptoms and cognitive impairments in hosts. These effects are linearly correlated with the expression levels of the host dopamine receptor D2 (DRD2). Furthermore, the behavioral abnormalities can be alleviated by treatment with the DRD2 agonist bromocriptine. Both in vivo and in vitro infection models revealed that the downregulation of DRD2 is significantly correlated with neuroinflammation and neuronal injury in the host central nervous system (CNS). Additionally, our findings suggest that the suppression of DRD2 may be regulated by enhanced RNA m6A modification following infection and may function through the DRD2/CRYAB/NF-κB signaling axis. These results emphasized the critical role of DRD2 in mediating T. gondii-induced neuroinflammation and neuropsychiatric abnormalities, providing novel insights into the development of therapeutic strategies for neuropsychiatric disorders associated with parasitic infections.
    Keywords:  Behavioral disorders; Dopamine receptor D2 (DRD2); M(6)A; Neuroinflammation; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.bbi.2025.106136
  2. J Cell Biol. 2025 Dec 01. pii: e202312109. [Epub ahead of print]224(12):
    Tepsin and AP4 mediate transport from the trans-Golgi to the plant-like vacuole in toxoplasma.
    Janessa Grech, Abhishek Prakash Shinde, Javier Periz, Mirko Singer, Simon Gras, Ignasi Forné, Andreas Klingl, Joel B Dacks, Elena Jiménez-Ruiz, Markus Meissner.
      Apicomplexan parasites are obligate intracellular pathogens possessing unique organelles but lacking several components of the membrane trafficking machinery conserved in other eukaryotes. While some of these components have been lost during evolution, others remain undetectable by standard bioinformatics approaches. Using a conditional splitCas9 system in Toxoplasma gondii, we previously identified TGGT1_301410, a hypothetical gene conserved among apicomplexans, as a potential trafficking factor. Here, we show that TGGT1_301410 is a distant ortholog of T. gondii tepsin (TgTEP), localized to the trans-Golgi and functioning as an accessory protein of the adaptor protein complex 4 (AP4). We demonstrate that AP4-TgTEP is essential for the actin-dependent transport of vesicles to the plant-like vacuole (PLVAC) and Golgi organization. Notably, our findings reveal that, unlike in metazoans, the AP4 complex in T. gondii utilizes clathrin as a coat protein, a mechanism more closely aligned with that of plants. These results underscore a conserved yet functionally adapted vesicular transport system in Apicomplexa.
    DOI:  https://doi.org/10.1083/jcb.202312109
  3. Cells. 2025 Sep 24. pii: 1495. [Epub ahead of print]14(19):
    NAD+ Homeostasis and Autophagy: Integrated Control Through Nutrient Signaling in Yeast and Mammals.
    Matilda McDaniel, Lan-Hsuan Lee, Su-Ju Lin.
      Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite facilitating redox and biochemical reactions in many cellular processes. Maintaining NAD+ homeostasis is critical for proper cellular function, and abnormalities in NAD+ metabolism have been associated with various human diseases. However, the mechanisms underlying its regulation and interconnection with nutrient-sensing pathways remain incompletely understood. Recent studies show that autophagy, a conserved catabolic pathway essential for cellular homeostasis, plays an important role in maintaining the NAD+ pool. NAD+ may also impact autophagy through its regulation of cellular metabolism and sirtuins, a family of NAD+-dependent deacetylases. Given the complexity of these pathways, their mechanistic interconnection is not fully understood. Here, we discuss studies examining the interactions of NAD+ metabolism, autophagy, and nutrient-sensing pathways, with a focus on the budding yeast Saccharomyces cerevisiae and connections to mammalian systems. We also discuss the role of sirtuins in these pathways and the impacts of NAD+ precursor supplementation. This review provides insights into how nutrient-sensing pathways may mediate the co-regulation of NAD+, autophagy, and cellular homeostasis. The studies discussed provide the basis for the development of future research directions that may inform potential therapeutic targets for human disorders associated with the dysregulation of NAD+ metabolism and autophagy.
    Keywords:  NAD+; autophagy; nutrient sensing; sirtuin
    DOI:  https://doi.org/10.3390/cells14191495
  4. J Chem Inf Model. 2025 Oct 13.
    Tandem Allosteric Effects of Reactant and Product that Promote Deacetylation Cycles in Sir2.
    Zhen Bai, Duy Phuoc Tran, Akio Kitao.
      Post-translational modifications play important roles in the regulation of protein function, with Nε acetylation being a key reversible modification affecting processes such as transcription, metabolism, and stress responses. Sirtuins, particularly SIRT1 and its ortholog, Sir2, are NAD+-dependent deacetylases that target both histone and nonhistone proteins, including the tumor suppressor p53. Acetylation of p53 on K382 influences its degradation and transcriptional activity. Despite structural studies of the Sir2/acetylated p53 complex, the role of the conserved cofactor-binding loop (CBL) in regulating NAD+ binding and deacetylation remains unclear. Using both conventional molecular dynamics (MD) and parallel cascade selection MD (PaCS-MD) simulations, we investigated the conformational dynamics of the Sir2/acetylated and nonacetylated p53 complexes, focusing on the conformational changes in the CBL of Sir2 in response to p53 acetylation. We identified open and closed states of the NAD+ binding pocket caused by CBL conformational changes depending on p53 acetylation and deacetylation. The forward allosteric effect of the acetylated p53 binding was found to open the NAD+-binding pocket, which is expected to promote NAD+ binding. In contrast, the binding of nonacetylated p53 is significantly weaker, and the reverse allosteric effect drives the pocket closure. These sequential allosteric effects positively accelerate the reaction cycle, which can be considered a "tandem allostery of the reactant (acetylated p53) and the product (deacetylated p53)". Combining these simulations with entropy transfer analysis, K382 was found to initiate multiple communication routes through strands β7 and β9, and the FEG loop, ultimately converging on the CBL via the helical small domain, the Rossmann-fold domain, or directly from p53, thereby highlighting the critical role of CBL in NAD+ binding and p53 deacetylation.
    DOI:  https://doi.org/10.1021/acs.jcim.5c01755
  5. Amino Acids. 2025 Oct 17. 57(1): 49
    Lysine malonylation as a therapeutic target: implications for metabolic, inflammatory, and oncological disorders.
    Ahsanullah Unar.
      Lysine malonylation (Kmal) is an emerging posttranslational modification (PTM) intricately linked to cellular metabolism and disease pathogenesis. This review explores the regulatory mechanisms of Kmal, emphasizing the role of malonyl-CoA as its donor substrate and Sirtuin 5 (SIRT5) as its primary demalonylase. Kmal significantly influences metabolic homeostasis, inflammation, and cancer by modifying key enzymes involved in glycolysis, fatty acid oxidation, and mitochondrial function. In metabolic disorders such as type 2 diabetes and obesity, aberrant malonylation contributes to insulin resistance, lipid accumulation, and oxidative stress. Inflammatory conditions, including sepsis and autoimmune diseases, involve malonylation-driven regulation of immune responses, particularly through GAPDH-mediated cytokine translation. Furthermore, in oncogenesis, malonylation plays a dual role: it suppresses tumor growth by impairing metabolic flux while also being exploited by cancer cells to maintain proliferation. Therapeutic interventions targeting Kmal include SIRT5 modulators, malonyl-CoA metabolism regulators, and small-molecule inhibitors that modulate lysine acylation dynamics. Advances in mass spectrometry and proteomics have expanded our understanding of the biological functions of Kmal; however, its full physiological and pathological significance remains under investigation. Future research should focus on elucidating tissue-specific malonylation patterns and their interactions with other PTMs to refine therapeutic strategies. By integrating metabolic regulation with disease mechanisms, Kmal has emerged as a crucial biochemical modification with broad implications for metabolic, inflammatory, and oncological disorders. Understanding its regulatory network will be pivotal in developing precision medicine approaches aimed at mitigating disease progression and restoring cellular homeostasis.
    Keywords:  Lysine malonylation; Malonyl-CoA; Metabolic regulation; Posttranslational modification; Sirtuin 5
    DOI:  https://doi.org/10.1007/s00726-025-03483-0
  6. Epigenomics. 2025 Oct 16. 1-16
    Epigenetic landscape of Leishmania-host interactions.
    Shweta Khandibharad, Shailza Singh.
      Leishmaniasis is a complex immuno-metabolic infectious disease regulated by epigenetic mechanisms in both the parasite and host. Epigenetic modifications such as chromatin remodeling, histone post-translational modifications (PTMs), and non-coding RNAs (ncRNAs) modulate gene expression to promote parasite survival and alter host immune responses. This review highlights species-specific epigenetic changes across Leishmania species contributing to pathogenesis and explains how the parasite manipulates host immune signaling through epigenetic pathways, including co-infection and co-morbidity models. Host factors like nuclear factor of activated T cells 5 (NFAT5) and Src homology 2 domain-containing phosphatase-1 (SHP-1), along with parasite-derived proteins such as Su(var)3-9, enhancer of zeste [E(z)], trithorax (SET) proteins, and histones, are emerging as promising epigenetic therapeutic targets. Furthermore, histone PTMs and transcription factors are critical epigenetic modifications supporting parasite survival. Synthetic gene circuits can modulate host and parasite epigenomes. Synthetic biology enables the assembly of genetic parts and pools to engineer cells with novel biological functions. A structured literature review using Web of Science, PubMed, and Scopus was performed, using keywords like epigenetics of Leishmania, epigenetics alterations in host with leishmaniasis, Leishmania and comorbidity and disease-specific terms. This review underscores the future potential of epigenetics and synthetic biology-based strategies in controlling leishmaniasis.
    Keywords:  Epigenetics; PTMs; co-infection; histones; therapeutics
    DOI:  https://doi.org/10.1080/17501911.2025.2574836
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