bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2025–10–12
twenty papers selected by
Lakesh Kumar, BITS Pilani
  1. Induced necroptosis limits Toxoplasma gondii replication in a RIPK3/MLKL-dependent manner.
  2. Reconsidering the Toxoplasma gondii interactome: opportunities beyond crosslinking mass spectrometry.
  3. MIC13 of Toxoplasma gondii: Potential Gene for Vaccine Candidate-An In Silico Approach.
  4. Beyond Rejection: Exploring Tacrolimus's Hidden Potential in Toxoplasmosis.
  5. Toxoplasma gondii, babesia, and other protozoan carbonic anhydrases.
  6. Toxoplasma gondii-induced adverse pregnancy outcomes: insight into the inhibitory role of Trem2 on TLR4/TRAF6/JNK signaling pathway.
  7. Toxoplasma gondii VIP1 mediates parasitophorous vacuole-host endoplasmic reticulum interactions to facilitate parasite development.
  8. Sirtuin 6 is a histone delactylase.
  9. Modest Protective Immune Responses Induced by a DNA Vaccine Expressing IMP1 of Toxoplasma gondii in BALB/c Mice.
  10. Toxoplasma gondii infection in the endangered Amami Woodcock, Scolopax mira (Aves: Charadriiformes).
  11. Reply to Rattanapitoon et al., "Reconsidering the Toxoplasma gondii interactome: opportunities beyond crosslinking mass spectrometry".
  12. Metabolic clash of Cryptosporidium and its host.
  13. Research progress on sirtuin family genes in colorectal cancer.
  14. Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.
  15. Plasmodium falciparum η-carbonic anhydrase.
  16. A cancer-specific antigen drives histone acetylation by stabilizing the acetyltransferases.
  17. Beyond the linker: Histone H1 as a dynamic epigenetic hub governing chromatin plasticity and disease pathogenesis.
  18. Toxoplasma gondii infection diagnosed by tNGS in a patient with acute lymphoblastic leukemia: a case report.
  19. A multi-omics analysis unveils functional and regulatory links between hydroxybenzene and aromatic amino acid metabolism in Candida albicans.
  20. The regulatory mechanisms and treatment of HDAC6 in immune dysregulation diseases.
  1. Infect Immun. 2025 Oct 07. e0047925
    Induced necroptosis limits Toxoplasma gondii replication in a RIPK3/MLKL-dependent manner.
    Billy J Erazo, Laura J Knoll.
      Toxoplasma gondii is an obligate intracellular parasite capable of subverting host defenses to establish infection. Necroptosis, a lytic pro-inflammatory form of programed cell death, has emerged as a host defense mechanism against intracellular pathogens. However, its relevance in controlling T. gondii replication remains unclear. Here, we investigated the role of necroptosis in limiting T. gondii replication using bone marrow-derived macrophages (BMDMs) deficient in key necroptotic mediators, RIPK3 and MLKL. We demonstrate that under naïve conditions, T. gondii replication proceeds unimpeded in RIPK3-/- and MLKL-/- BMDMs. However, co-treatment with TNF-α and the pan-caspase inhibitor Z-VAD-FMK, conditions that promote necroptosis, significantly reduced parasite replication in wild-type BMDMs but not in those lacking RIPK3 or MLKL. This suppression was dependent on RIPK1 activity, as pharmacological inhibition with Necrostatin-1 abrogated the effect. We further confirmed that TNF-α and Z-VAD-FMK treatment induced necroptotic cell death characterized by loss of plasma membrane integrity, both of which were absent in RIPK3-/- and MLKL-/- cells. These findings establish that the activation of necroptosis can effectively limit T. gondii replication in BMDMs and underscore the importance of RIPK1-RIPK3-MLKL signaling in mounting a cell-intrinsic immune defense. Our study provides new insight into the functional capacity of necroptosis in restricting intracellular parasites and highlights its potential as a therapeutic target in toxoplasmosis.
    Keywords:  Toxoplasma gondii; apoptosis; necroptosis; programmed cell death
    DOI:  https://doi.org/10.1128/iai.00479-25
  2. mBio. 2025 Oct 09. e0268325
    Reconsidering the Toxoplasma gondii interactome: opportunities beyond crosslinking mass spectrometry.
    Nathkapach K Rattanapitoon, Patpicha Arunsan, Nav La, Schawanya K Rattanapitoon.
      
    Keywords:  Toxoplasma gondii; crosslinking mass spectrometry; dense granule proteins; interactive; machine learning
    DOI:  https://doi.org/10.1128/mbio.02683-25
  3. J Parasitol Res. 2025 ;2025 3114690
    MIC13 of Toxoplasma gondii: Potential Gene for Vaccine Candidate-An In Silico Approach.
    Mahdi Khadem Mohammadi, Ali Dalir Ghaffari.
      Purpose: Toxoplasmosis, which is the result of infection by Toxoplasma gondii (T. gondii), is a widespread parasitic disease that affects approximately one-third of the global population. Routine medications are not able to eradicate the parasites enclosed in cysts that reside inside the hosts that are infected. MIC13 is believed to have a significant function in facilitating the dissemination of the parasite throughout the host organism. The objective of this research was to utilize immunoinformatics techniques for antigenic analysis and structural prediction of the MIC13 protein, with the goal of identifying potential epitopes that could be used to create a vaccine for T. gondii. Materials and Methods: The current research was aimed at describing the chemical and physical features, subcellular localization, potential epitopes for B- and T-cells, transmembrane domain, tertiary and secondary structures, and other attributes of the MIC13 protein. Results: The results indicated that the MIC13 protein possesses a single N-glycosylation, 15 O-glycosylation regions, 70 phosphorylation sites, and five acetylation sites, with no transmembrane domains being detected within its structure. In terms of secondary structure, the MIC13 protein is composed of 27.99% alpha-helix, 16.45% extended strand, and 55.56% random coil elements. Additionally, various potential B- and T-cell epitopes were pinpointed for the MIC13 protein, suggesting its immunogenic properties. The assessment of antigenicity and allergenicity further confirmed that MIC13 is immunogenic but nonallergenic, making it a promising candidate for further study. Furthermore, the induction of IFN-γ and IL-4 highlighted the ability of related MHC-II molecules to interact with MIC13, indicating its potential role in immune responses. These findings shed light on the multifaceted nature of the MIC13 protein and its significance in immunological processes. Conclusion: These findings suggest that MIC13 could serve as a key component in the creation of a successful vaccine targeting T. gondii. The results obtained from this research lay a solid foundation for future investigations and offer valuable insights for the creation of successful vaccines to combat both acute and chronic toxoplasmosis through diverse strategies.
    Keywords:  MIC13; Toxoplasma gondii; bioinformatics; vaccines
    DOI:  https://doi.org/10.1155/japr/3114690
  4. Cureus. 2025 Sep;17(9): e91721
    Beyond Rejection: Exploring Tacrolimus's Hidden Potential in Toxoplasmosis.
    Benjamin R Johnson, Anna K Potter.
      Human infection and treatment of Toxoplasma gondii, known as toxoplasmosis, pose unique challenges and risks, particularly in transplant recipients and immunocompromised individuals. Toxoplasma gondii is an apicomplexan protozoan parasite that has been defined as the most successful parasite, with infections ranging from asymptomatic to fatal. It is prevalent throughout the world, presenting higher morbidity and mortality in immunocompromised and immunosuppressed individuals. Tacrolimus is a calcineurin inhibitor, often serving a role in transplant medicine as an immunosuppressant. Cyclosporine is the other commonly used calcineurin inhibitor, with similarity to tacrolimus in its mechanism of action, and has shown to be effective in the treatment of several parasitic infections. Both of these drugs block the intracellular calcium signaling cascade mediated by calcineurin, through binding to their respective immunophilin proteins. Toxoplasma gondii is dependent on this pathway for cell lysis and its egress from the vacuole. Cyclosporine has presented antiparasitic activity both in vitro and in vivo against another protozoan parasite with similarities to T. gondii, Plasmodium falciparum, through its inhibition of this pathway. Given the functional similarities between cyclosporine and tacrolimus, this narrative review aims to assess the antiparasitic potential of tacrolimus, particularly considering the promising antiparasitic activity observed with cyclosporine and other calcineurin inhibitors. Further research is needed on this role in tacrolimus to evaluate its efficacy, safety, and other potentials in the management of toxoplasmosis, independently and in combination therapies.
    Keywords:  antiparasitic; calcineurin inhibitors; cyclosporin a; tacrolimus; toxoplasma gondii; toxoplasmosis
    DOI:  https://doi.org/10.7759/cureus.91721
  5. Enzymes. 2025 ;pii: S1874-6047(25)00006-X. [Epub ahead of print]57 183-206
    Toxoplasma gondii, babesia, and other protozoan carbonic anhydrases.
    Clemente Capasso, Claudiu T Supuran.
      Carbonic anhydrases (CAs) play an essential role in the physiology and survival of protozoan parasites. This study explores the biological functions, molecular features, and therapeutic potential of protozoan CAs, focusing on the α, β, and η classes. Emphasis is placed on the structural and functional divergences between protozoan and mammalian CAs, underscoring the opportunities for selective drug targeting. Key protozoan pathogens, including Toxoplasma gondii, Trypanosoma cruzi, Leishmania spp., Trichomonas vaginalis, Entamoeba histolytica and Plasmodium falciparum, are examined with respect to their CA classes, which are evaluated for their roles in parasite metabolism and as candidates for therapeutic intervention. The potential of CA inhibitors as novel antiparasitic agents was critically assessed. By integrating established findings with emerging data, this analysis offers a comprehensive framework for the strategic exploitation of protozoan CAs for the development of next generation antiparasitic therapies.
    Keywords:  Babesia; Carbonic anhydrase; Drug target; Leishmania spp.; Plasmodium falciparum; Protozoan parasites; Toxoplasma gondii; Trichomonas vaginalis; Trypanosoma cruzi
    DOI:  https://doi.org/10.1016/bs.enz.2025.05.004
  6. Parasit Vectors. 2025 Oct 06. 18(1): 396
    Toxoplasma gondii-induced adverse pregnancy outcomes: insight into the inhibitory role of Trem2 on TLR4/TRAF6/JNK signaling pathway.
    Yining Cao, Feifei Fu, Fei Ju, Chenyu Wu, Tiankun Yao, Mei Yang, Baolan Sun, Jinling Chen.
       BACKGROUND: Decidual macrophages (dMφs) are not only essential for maintaining normal pregnancy but also serve as crucial immune defenders against infections, including Toxoplasma gondii. Triggering receptor expressed on myeloid cells 2 (Trem2), as a critical immunoregulatory receptor on dMφs, can counteract inflammation and defend against pathogen infection. However, the mechanisms underlying the Trem2 downstream pathways during T. gondii infection-particularly their impact on adverse pregnancy outcomes (APOs)-remain elusive.
    METHODS: The interaction between Trem2 and Toll-like receptor 4 (TLR4) was initially predicted through molecular docking models and subsequently confirmed by co-immunoprecipitation, using both animal models and cellular systems to examine the impact of Trem2 knockout, overexpression, and TLR4-blocking antibody treatment on downstream signaling molecules as well as cytokine production.
    RESULTS: The interaction between Trem2 and TLR4 was validated. Trem2 downregulation during T. gondii infection coincided with increased TLR4, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), and c-Jun N-terminal kinase (JNK) activation, while Trem2 knockout further enhanced TLR4/TRAF6/JNK signaling in mice and macrophages. Conversely, Trem2 overexpression suppressed this signaling cascade and reversed T. gondii-induced activation. Treatment with a TLR4-blocking antibody inhibited TRAF6 and P-JNK activation in macrophages but did not affect Trem2 expression. Additionally, Trem2-deficient bone marrow-derived macrophages (BMDMs) exhibited elevated transcription of TNF-α and interferon-γ (IFN-γ) upon T. gondii antigen stimulation.
    CONCLUSIONS: Trem2 deficiency in pregnant mice promotes the TLR4/TRAF6/JNK signaling cascade following T. gondii infection. This study demonstrates that Trem2 acts as a pregnancy-specific inhibitor of TLR4/TRAF6/JNK signaling, providing novel mechanistic insights into T. gondii-induced APOs.
    Keywords:   Toxoplasma gondii ; Adverse pregnancy outcomes; Macrophages; TLR4/TRAF6/JNK signaling pathway; Triggering receptor expressed on myeloid cells 2
    DOI:  https://doi.org/10.1186/s13071-025-07000-w
  7. Nat Microbiol. 2025 Oct 10.
    Toxoplasma gondii VIP1 mediates parasitophorous vacuole-host endoplasmic reticulum interactions to facilitate parasite development.
    Julia D Romano, Ruth Buh, Tanner Grudda, Julia R Box, John Beltran, Shahbaz M Khan, Isabelle Coppens.
      Membrane contact sites (MCS) are areas of close apposition between organelles without membrane fusion, allowing for exchange of biomolecules. The endoplasmic reticulum (ER) forms many MCS via two proteins, vesicle-associated membrane protein-associated proteins A and B (VAPA and VAPB). The obligate intracellular parasite Toxoplasma gondii resides within mammalian cells in a parasitophorous vacuole (PV), which closely contacts the host ER at distances compatible with MCS. However, the proteins mediating this interaction remain largely unknown. Here, using molecular and microscopy approaches, we show that VAPA and VAPB localize at the PV membrane and, with motile sperm domain-containing protein 2 (MOSPD2), mediate ER-PV interactions. Cells deficient in VAPA, VAPB and MOSPD2 do not recruit host ER at the PV, and parasites show growth defects. We identify a parasite protein that localizes at the PV membrane, called TgVIP1, which harbours an FFAT-like motif that binds VAPA and VAPB. These findings lay the basis for understanding how and why Toxoplasma exploits ER-PV interactions and may uncover new drug targets.
    DOI:  https://doi.org/10.1038/s41564-025-02144-y
  8. J Biol Chem. 2025 Oct 06. pii: S0021-9258(25)02647-X. [Epub ahead of print] 110795
    Sirtuin 6 is a histone delactylase.
    Garrison A Nickel, Nicholas J Pederson, Faheem, Zhenyu Yang, Jack Bulf, Katharine L Diehl.
      Histone lactylation (Kla) is a post translational modification (PTM) that is derived from metabolic lactate. Histone Kla has been extensively studied in the field of inflammation resolution and macrophage polarization but has also been implicated in diverse cellular processes including differentiation, various wound repair phenotypes, and oncogenesis in several cancer models. While mechanistic connections between histone Kla and transcriptional changes have been studied in very limited contexts, general mechanistic details describing how regulation of gene expression by histone Kla occurs are scarce. It is hypothesized that histone Kla may be installed either through nonenzymatic means or by acetyltransferases like p300, and it is known that Class I HDACs and Sirtuins 1-3 can remove histone Kla. Here, we identified histone delactylase activity of the deacylase enzyme Sirtuin 6 (Sirt6), a member of the Class III HDAC family known to have roles in regulating metabolic homeostasis. We characterized the ability of Sirt6 to delactylate histones in vitro and in a mammalian cell culture model. We identified H3K9 and H3K18, canonical histone sites of Sirt6-catalyzed deacetylase activity, as sites of its delactylase activity. We also demonstrated that Sirt6 and the Class I HDACs exhibit some degree of non-overlapping delactylase activity, suggesting that they represent different cellular axes of regulating gene expression via controlling levels of histone Kla.
    Keywords:  Histone deacetylase; epigenetics; histone lactylation; histone modifications; lactic acid; sirtuin
    DOI:  https://doi.org/10.1016/j.jbc.2025.110795
  9. Parasite Immunol. 2025 Oct;47(10): e70025
    Modest Protective Immune Responses Induced by a DNA Vaccine Expressing IMP1 of Toxoplasma gondii in BALB/c Mice.
    Farid Alizadeh, Maryam Hataminejad, Hajar Yaghoobi, Hakim Azizi.
      Toxoplasma gondii is a parasitic protozoan that infects nucleated cells and poses a major threat to human and animal health. Developing effective vaccines is critical for controlling toxoplasmosis. Immune Mapped Protein 1 (IMP1) is a protective antigen located on the plasma membrane of T. gondii. This study aimed to evaluate the efficacy of IMP1 as a DNA vaccine, either alone or combined with IL-12 as an adjuvant, in BALB/c mice. The use of IL-12 as an adjuvant was based on its well-documented ability to enhance Th1 immune responses in DNA vaccines against T. gondii. Mice were divided into five groups: group I served as a control (100 μL PBS), group II received empty pcDNA3.1, group III received pcIL12, group IV received pcTgIMP1, and group V received a combination of pcTgIMP1 and pcIL12 (50 μg each). Immunisation was administered three times on days zero, 14, and 28 with the same dose. Two weeks post-final vaccination, mice from each group were either challenged with a lethal dose of T. gondii for survival monitoring or euthanised for evaluating immune responses, including antibody levels, lymphocyte proliferation, and cytokine production. Results showed that mice immunised with pcIMP1 + pcIL-12 or pcTgIMP1 alone exhibited robust immune responses against Toxoplasmosis. These responses included elevated levels of IgG1 and IgG2a antibodies, a strong lymphoproliferative response, and higher levels of IFN-γ and IL-4 production compared to the other groups. Furthermore, mice immunised with pcIMP1 + pcIL-12 demonstrated prolonged survival times compared to the empty pcDNA3.1, pcIL-12 alone, and control groups (p < 0.05). Our finding underscores the potential of IMP1 as a vaccine candidate and highlights the adjuvant effect of IL-12 in enhancing protective immunity against toxoplasmosis.
    Keywords:   Toxoplasma gondii ; BALB/c mice; DNA vaccine; IMP1
    DOI:  https://doi.org/10.1111/pim.70025
  10. Int J Parasitol Parasites Wildl. 2025 Dec;28 101135
    Toxoplasma gondii infection in the endangered Amami Woodcock, Scolopax mira (Aves: Charadriiformes).
    Ryotaro Suzuki, Toshihiro Tokiwa, Keiko Ito, Ryouta Torimoto, So Shinya, Makoto Haritani, Masami Yamamoto, Hisashi Yoshimura.
      Toxoplasma gondii is a parasitic protozoan for which family Felidae serves as the definitive hosts. In regions where native felids are absent, introduced domestic cats (Felis catus) act as reservoirs of T. gondii, posing a threat of infection to various wildlife population. A population of feral cats has been identified on Amami-Oshima Island located in the southern part of the Japanese Archipelago, and molecular examination confirmed that the T. gondii they harbour has spread to endemic mammals. In this study, we aimed to detect T. gondii in the Amami Woodcock (Scolopax mira), a bird species endemic to Amami-Oshima Island. DNA was extracted from the brain tissue of twenty-two birds, and molecular detection of T. gondii was performed using a commercial T. gondii detection kit based on real-time polymerase chain reaction. Two birds (9.1%) tested positive. The determined nucleotide sequences were 100% identical to that of the T. gondii reference sequence. Histopathological examination and ultrastructural analyses revealed terminal colonies in the cardiomyocytes of one bird, which were immunohistochemically confirmed as T. gondii. Here, we report the first record of T. gondii infection in the Amami Woodcock. Given its endangered status, ongoing research on the prevalence and pathogenicity of T. gondii is warranted.
    Keywords:  Alien parasite; Amami Woodcock; Amami-oshima island; Endemic species; Japan; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.ijppaw.2025.101135
  11. mBio. 2025 Oct 09. e0275025
    Reply to Rattanapitoon et al., "Reconsidering the Toxoplasma gondii interactome: opportunities beyond crosslinking mass spectrometry".
    Tadakimi Tomita, Elizabeth Weyer, Rebekah Guevara, Simone Sidoli, Jennifer T Aguilan, Louis M Weiss.
      
    DOI:  https://doi.org/10.1128/mbio.02750-25
  12. Cell Host Microbe. 2025 Oct 08. pii: S1931-3128(25)00377-4. [Epub ahead of print]33(10): 1647-1649
    Metabolic clash of Cryptosporidium and its host.
    Simona Seizova, Christopher J Tonkin.
      In recent papers published in Cell and Cell Host and Microbe, Marzook et al. and Huang et al. investigate how Cryptosporidium, an enteric parasite, can acquire nutrients from its host and deals with potentially toxic products. These studies highlight that transporters are likely key to the success of this parasite.
    DOI:  https://doi.org/10.1016/j.chom.2025.09.011
  13. Front Oncol. 2025 ;15 1570030
    Research progress on sirtuin family genes in colorectal cancer.
    Tong Liu, Tianhua Wu, Lijun Luo, Wei Li, Minglin Zhang.
      Sirtuins are a highly conserved family of NAD+-dependent deacetylases involved in regulating critical biological processes such as cell survival, antioxidation, gene transcription, proliferation, differentiation, DNA repair, and mitochondrial function. Recent studies have revealed that altered expression of sirtuin family genes in mammals is closely linked to the development of various diseases, including metabolic disorders, ageing, and cancer. In colorectal cancer (CRC), sirtuins play dual regulatory roles, modulating tumour cell proliferation, migration, invasion, and apoptosis while also activating pro-oncogenic signalling pathways or suppressing tumour progression, depending on context. This review systematically summarizes the research progress on sirtuin family genes in CRC, highlighting their dual roles (pro-tumorigenic and tumour-suppressive) and molecular mechanisms. These findings underscore the potential of sirtuins as therapeutic targets in CRC. The development of selective activators or inhibitors, combined with metabolic interventions or immunotherapy, may provide novel strategies for precision CRC treatment.
    Keywords:  colorectal cancer; epigenetic regulation; metabolic reprogramming; sirtuin family; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2025.1570030
  14. Cell Host Microbe. 2025 Oct 08. pii: S1931-3128(25)00363-4. [Epub ahead of print]33(10): 1645-1647
    Metabolic tug-of-war: Mitochondria starve Toxoplasma of folate.
    Evie R Hodgson, Diana Stojanovski.
      In a recent Science paper, Medeiros et al. describe how infected cells use mitochondria as metabolic guardians, outcompeting Toxoplasma parasites for folate, an essential vitamin for DNA synthesis. This metabolic immunity strategy transforms the cell's powerhouse to an active defender, sequestering nutrients away from invaders in a metabolic tug-of-war.
    DOI:  https://doi.org/10.1016/j.chom.2025.09.002
  15. Enzymes. 2025 ;pii: S1874-6047(25)00004-6. [Epub ahead of print]57 113-127
    Plasmodium falciparum η-carbonic anhydrase.
    Claudiu T Supuran, Clemente Capasso.
      Malaria parasites belonging to the genus Plasmodium encode for a carbonic anhydrase (CA, EC 4.2.1.1) originally considered to belong to the α-class, which has been investigated starting with 2004 as a potential antimalarial target, considering the observation that CA levels in red blood cells infected with these parasites are much higher compared to those of uninfected cells. In plasmodia, CA is involved in metabolic pathways leading to the biosynthesis of pyrimidines, which are scarcely present in the blood of infected hosts, making this enzyme crucial for the life cycle of the parasite in many intraerythrocytic stages of its development. It has been then shown in 2014 that P. falciparum CA (PfCA) belongs in fact to a new CA genetic class, the η-CA, characterized by a particular zinc ion coordination within the active site, with two histidine and a glutamine as protein ligands. A short, truncated and longer PfCA forms have been cloned and characterized in detail, being shown that they act as efficient catalysts for the hydration of CO2 to bicarbonate and protons, but neither of them were crystallized for the moment, and their 3D structure is not known. PfCA inhibition with anions, sulfonamides, phenols and coumarins has been investigated too, with many low nanomolar in vitro inhibitors being detected. Only for acetazolamide and an ureido-substituted benzenesulfonamide it has been demonstrated a potent growth inhibition of the pathogen in P. falciparum infected red blood cells. Although these results are encouraging but rather preliminary, η-CAs from malaria-producing protozoans and presumably other organisms encoding them, may be considered as innovative drug targets for obtaining anti-infectives with new mechanisms of action but these enzymes should be investigated in more details in order to better understand their structure and physiological/pathological roles.
    Keywords:  Carbonic anhydrase; Drug targets; Plasmodium falciparum; Protozoa; Pyrimidines metabolism
    DOI:  https://doi.org/10.1016/bs.enz.2025.05.002
  16. Cell Rep. 2025 Oct 07. pii: S2211-1247(25)01179-9. [Epub ahead of print]44(10): 116408
    A cancer-specific antigen drives histone acetylation by stabilizing the acetyltransferases.
    Xuekun Fu, Xu Yang, Jie Huang, Yuhong Huang, Patrick Ryan Potts, Chao Liang.
      Histone acetylation is a critical modification that regulates gene expression by modulating chromatin structure and function. Histone acetyltransferases are essential for maintaining acetylation homeostasis, and the disruption of this balance can lead to aberrant gene expression and cancer development. Here, we describe that the cancer-specific protein MAGE-A10 increases cellular histone acetylation by stabilizing essential histone acetyltransferases KAT2A and KAT2B. The aberrant expression of MAGE-A10 in tumors prevents the degradation of KAT2A/2B through p62-mediated autophagy. Mechanistically, MAGE-A10 antagonizes the binding of KAT2A/2B with the E3 ubiquitin ligase complex CUL4A-DDB1, thereby decreasing the formation of their K63-linked ubiquitination. Furthermore, KAT2A enhances the transcription of the MAGE-A10 gene, forming a positive feedback loop that contributes to tumorigenesis. These findings provide insights into the molecular mechanisms hijacked in cancer that drive perturbed histone acetylation and suggest potential therapeutic strategies.
    Keywords:  CP: Cancer; CP: Molecular biology; KAT2A; KAT2B; MAGE-A10; cancer; ubiquitintion
    DOI:  https://doi.org/10.1016/j.celrep.2025.116408
  17. Int J Biol Macromol. 2025 Oct 04. pii: S0141-8130(25)08662-3. [Epub ahead of print] 148105
    Beyond the linker: Histone H1 as a dynamic epigenetic hub governing chromatin plasticity and disease pathogenesis.
    Yue Liu, Keyi Liang, Siqi Jiang, Qiutong Chen, Lida Cheng, Nan Xu, Xin Wei, Qianru Xu, Su Chen.
      Chromatin, a higher-order structure of eukaryotic genomes, is dynamically regulated and plays pivotal roles in gene regulation and cellular homeostasis. Nucleosomes are the basic functional units of chromatin. Each nucleosome consists of a histone octamer (H2A, H2B, H3, and H4) wrapped by DNA. While linker histone H1 (H1) facilitates and stabilizes DNA binding to histones, it also critically governs higher-order chromatin organization and transcriptional regulation. Although post-translational modifications (PTMs) of core histones have been extensively characterized, the functional significance of H1 has historically been underappreciated. Emerging research reveals that H1 is not merely a structural component but a dynamic epigenetic regulator governing chromatin higher-order organization, transcriptional programs, and cellular differentiation. H1 undergoes diverse post-translational modifications, including acetylation, methylation, phosphorylation, and ubiquitination, which fine-tune its interactions with chromatin and non-chromatin partners. Dysregulation of H1 expression, localization, or PTMs is implicated in cancer, neurodegenerative disorders, metabolic diseases, and immune dysfunctions. This review synthesizes recent advances in H1 biology, highlighting its isoform-specific functions, PTM-mediated regulatory networks, and translational potential as a diagnostic marker and therapeutic target.
    Keywords:  Chromatin higher-order structure; Histone H1; Post-translational modifications; Therapeutic target; Transcriptional regulation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148105
  18. BMC Infect Dis. 2025 Oct 10. 25(1): 1287
    Toxoplasma gondii infection diagnosed by tNGS in a patient with acute lymphoblastic leukemia: a case report.
    Fengfan Li, Wei He, Kexin Ren, Jiefei Chen, Jialiang Zhang, Xin Liu, Ziyang Li, Min Hu.
      
    Keywords:  Case report; Precision treatment; Targeted next-generation sequencing; Toxoplasma gondii; Trimethoprim-sulfamethoxazole
    DOI:  https://doi.org/10.1186/s12879-025-11771-z
  19. mSystems. 2025 Oct 08. e0022625
    A multi-omics analysis unveils functional and regulatory links between hydroxybenzene and aromatic amino acid metabolism in Candida albicans.
    Enrico Garbe, Sascha Schäuble, Bettina Böttcher, Robert Jesse, Dominik Driesch, Lasse van Wilijck, Osama Elshafee, Tim Bastian Schille, Bernhard Hube, Gianni Panagiotou, Slavena Vylkova.
      The fungus Candida albicans is a frequent colonizer of humans but also an opportunistic pathogen causing superficial to severe infections, especially in vulnerable individuals. Its broad metabolic flexibility is key for the fungal adaptation to host environments, evasion from immune attack, and virulence. Amino acid metabolism and homeostasis, in particular, are critical for fungal fitness-illustrated by a rapid metabolic shift in response to amino acid starvation to restore intracellular metabolic balance. To investigate the cellular mechanisms underlying such compensatory metabolic processes, we performed data-driven genome-scale metabolic modeling based on transcriptional metabolic profiles of amino acid-starved cells to identify condition-specific fungal metabolic fluxes and pathway activities specific to cellular response to amino acid starvation. Most prominently, we predicted altered activity of the shikimate pathway upon amino acid limitation and identified a simultaneous induction of aromatic amino acid (AAA) biosynthesis and a metabolic gene cluster required for the catabolism of hydroxybenzenes. Further phenotypic and transcriptional analyses not only verified the transcription factor Zcf25 as the central regulator of the catechol-branch of this pathway, but also condition-specific co-regulation of AAA and hydroxybenzene metabolism mediated by Zcf25 and the transcriptional regulator of amino acid metabolism Stp2. These findings propose a so far unknown metabolic link between amino acid and hydroxybenzene metabolism in C. albicans, therewith adding another layer to its metabolic plasticity.
    IMPORTANCE: The opportunistic human fungal pathogen Candida albicans possesses a remarkable metabolic plasticity, which is essential for both fungal commensalism and virulence and influences its physiology and behavior in multiple ways. The investigation of such processes particularly benefits from the emergence of multi-omics and in silico approaches. In this study, we combined a multi-omics approach with genome-scale metabolic modeling to investigate the fungal metabolic adaptation to amino acid utilization and starvation. Most strikingly, we found an altered activity of the shikimate pathway upon amino acid starvation, accompanied by a simultaneous induction of two metabolic gene clusters required for the metabolism of hydroxybenzenes. Further analyses revealed so far unknown potential functional and regulatory links between both metabolic pathways, which provide starting points for future research leading to a better understanding of the fungal adaptation to dynamic host conditions.
    Keywords:  3-oxoadipate pathway; Candida albicans; amino acid metabolism; genome-scale metabolic modeling; metabolomics; shikimate pathway
    DOI:  https://doi.org/10.1128/msystems.00226-25
  20. Front Immunol. 2025 ;16 1653588
    The regulatory mechanisms and treatment of HDAC6 in immune dysregulation diseases.
    Yanyang Liang, Ying Wang, Jianxiao Xing, Junqin Li, Kaiming Zhang.
      Histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase that contains two catalytic domains and a zinc finger ubiquitin binding domain (ZnF-UBP). The deacetylation function of HDAC6 has been extensively studied with well-characterized substrates such as α-tubulin and Hsp90. Apart from its deacetylase activity, HDAC6 ZnF-UBP binds to unanchored ubiquitin of specific sequences and serves as a carrier for transport of aggregated proteins. subsequently, aggresomes is degraded by the autophagy-lysosome pathway. Additionally, Cells can utilize this HDAC6-dependent microtubule transport to assemble and activate inflammasomes, which play a critical role in immune regulation. HDAC6 displays a unique structure and cellular localization as well as diverse substrates, and exhibits a wider range of biological functions than other HDAC isoforms. HDAC6 has been intimately linked to a spectrum of diseases, including rheumatoid arthritis, systemic lupus erythematosus, psoriasis, neuritis, and the cancer immune microenvironment. This review systematically synthesizes the current research advancements of HDAC6, focusing on three key dimensions: the mechanism of action of HDAC6, therapeutic advancements, and translational prospects in clinical applications.
    Keywords:  HDAC6; autoimmune diseases; cancer immunotherapy; immune regulation; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2025.1653588
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