bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2026–03–01
nineteen papers selected by
Lakesh Kumar, BITS Pilani
  1. Evolutionary Remodeling of Ubiquinone Biosynthesis in Toxoplasma gondii Reveals an Essential Bi-functional Monooxygenase.
  2. The Centrocone Protein SMC_N1 Is Important for the Proliferation of Toxoplasma gondii Tachyzoites.
  3. Loss of TGME49_227100 (Glutaredoxin 5) Disrupts Oocyst Formation and Sporulation in Toxoplasma gondii.
  4. Two anchoring proteins control daughter apical complex assembly in Toxoplasma gondii.
  5. Comparison of two DNA extraction methods for the detection of zoonotic protozoan pathogens in oysters and seawater.
  6. Genome-wide transcriptomic analysis of Toxoplasma gondii reveals stage-specific regulatory programs and metabolic adaptations driving oocyst sporulation.
  7. Shifting metabolism alters rRNA expression in malaria parasites.
  8. The effect of Toxoplasma gondii infection in parental male mice on the transcriptome of their offspring's brain.
  9. A protein adaptor mediating Ap4A-dependent control of protein acetylation.
  10. The promoter-poised Rpd3 HDAC complex orchestrates global chromatin reprogramming upon nutrient transition.
  11. Non-hydrolyzable acetyllysine analogs to study protein acetylation in vitro and in cells.
  12. Protein arginine methyltransferases in protozoan parasites: a new path for antiparasitic chemotherapy?
  13. Lactate metabolism and protein lactylation in cancer.
  14. Tubulin acetylation governs organelle remodeling and lysosomal reformation during neuronal differentiation.
  15. Plasmodium ARK1 regulates spindle formation during atypical mitosis and forms a divergent chromosomal passenger complex.
  16. UIP4 governs nuclear shape by modulating Saccharomyces cerevisiae lipidome.
  17. The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.
  18. ASCT2 palmitoylation regulated by JNK1-ZDHHC14 axis orchestrates glutamine metabolism and NSCLC progression.
  19. Metabolic plasticity of sphingolipids governs cancer cell fitness in acidic tumor ecosystems.
  1. bioRxiv. 2026 Feb 12. pii: 2026.02.10.705114. [Epub ahead of print]
    Evolutionary Remodeling of Ubiquinone Biosynthesis in Toxoplasma gondii Reveals an Essential Bi-functional Monooxygenase.
    Baihetiya Baierna, Taufiq Rahman, Scott Latimer, Gilles J Basset, Silvia Nj Moreno.
      Apicomplexan parasites like Toxoplasma gondii harbor a highly divergent mitochondrial proteome, much of which remains uncharacterized despite its essentiality for parasite survival. One such critical pathway is ubiquinone (UQ) biosynthesis. Here, we characterize the UQ synthesis machinery in T. gondii and show that conserved enzymes, TgCoq3 and TgCoq5, are essential for growth and mitochondrial function, forming a multi-protein complex. Using proximity labeling and subcellular fractionation, a strategy suited for detecting proteins of low abundance, we identify TgCoqFAD, a unique FAD-dependent monooxygenase required for UQ synthesis. Unlike canonical eukaryotic systems that employ multiple monooxygenases to modify specific carbons on the UQ aromatic ring, TgCoqFAD catalyzes two distinct hydroxylation steps, an activity not previously reported in eukaryotes. Molecular docking and chemical screening identified TgCoqFAD inhibitors that impair tachyzoite growth and bradyzoite viability. These findings reveal a streamlined and divergent UQ biosynthesis pathway in apicomplexans and establish TgCoqFAD as a promising antiparasitic target.
    DOI:  https://doi.org/10.64898/2026.02.10.705114
  2. Animals (Basel). 2026 Feb 18. pii: 653. [Epub ahead of print]16(4):
    The Centrocone Protein SMC_N1 Is Important for the Proliferation of Toxoplasma gondii Tachyzoites.
    Chuan Li, Jin Gao, Xiao-Jing Wu, Shi-Chen Xie, Hai-Sheng Zhang, Xing-Quan Zhu.
      The highly efficient endodyogeny of tachyzoites is a key process driving acute infection by Toxoplasma gondii. The centrocone is a specialized and critical structure for parasite cell division, but the regulatory mechanisms of centrocone proteins in T. gondii remain poorly understood. In this study, we characterized the centrocone protein SMC_N1, which exhibited periodic expression in tachyzoites, peaking during the synthesis phase. Conditional depletion of SMC_N1 was achieved in the type I RH strain and type II cyst-forming PRU strain using the mAID system combined with CRISPR-Cas9. Depletion of SMC_N1 disrupted IMC assembly, endodyogeny and nuclear division, as well as the stable inheritance of the apicoplast and centrosome, resulting in severe defects in intracellular replication and impaired tachyzoite growth. Collectively, these results indicate that SMC_N1 regulates cell division by coordinating organelle inheritance and cytoskeletal dynamics, ensuring proper replication of T. gondii tachyzoites and provide insights into mechanisms controlling parasite proliferation.
    Keywords:  Toxoplasma gondii; cell cycle; centrocone; endodyogeny; growth
    DOI:  https://doi.org/10.3390/ani16040653
  3. Pathogens. 2026 Jan 30. pii: 150. [Epub ahead of print]15(2):
    Loss of TGME49_227100 (Glutaredoxin 5) Disrupts Oocyst Formation and Sporulation in Toxoplasma gondii.
    Fujie Xie, Yuehua Xie, Yilin Yang, Chenxi Zhao, Jingxia Suo, Zhenzhao Zhang, Ruiying Liang, Xinming Tang, Xianyong Liu.
      Oocysts of Toxoplasma gondii exhibit remarkable resistance to environmental stressors and most conventional disinfectants. Despite its ability to infect a wide variety of host species, sexual reproduction and oocyst formation occur exclusively within felid definitive hosts. Despite the epidemiological significance of oocyst-mediated transmission, the molecular mechanisms governing oocyst production and sporulation remain incompletely understood. Glutaredoxin, serving as a central regulator of cellular redox homeostasis and multiple vital cellular processes in cells, is a potential regulator for oocyst sporulation. Here, we investigated the role of TGME49_227100 (glutaredoxin 5, Grx5) in the T. gondii Pru strain-a type II strain capable of oocyst formation, with a particular focus on its functions during oocyst formation and sporulation. We found that Grx5-knockout tachyzoites exhibited no defects in growth or virulence. Neither in vitro nor in vivo tachyzoite-to-bradyzoite differentiation was affected compared to wild-type parasites. Notably, Grx5 deletion significantly reduced oocyst production in cats by approximately 70%. Additionally, the collected oocysts showed a 50% decrease in sporulation rate. These results indicate that Grx5 plays a predominant role within feline host and the external environmental stage of sporulation, which of these is likely to provide a crucial molecular target for developing a transmission-blocking vaccine.
    Keywords:  Grx5; Toxoplasma gondii; oocyst; sporulation
    DOI:  https://doi.org/10.3390/pathogens15020150
  4. bioRxiv. 2026 Feb 14. pii: 2026.02.13.705759. [Epub ahead of print]
    Two anchoring proteins control daughter apical complex assembly in Toxoplasma gondii.
    Mélanie Burette, Marcin Pezinsky, Quynh Nguyen, Alae Benharoual, Sharon Patray, Marjorie Maynadier, Jason Delabre, Thomas Mouveaux, Arnault Graindorge, Laurence Berry, Jean-Francois Dubremetz, Valérie Rofidal, Yi-Wei Chang, Mathieu Gissot, Maryse Lebrun.
      During Toxoplasma gondii division, the apical complex-comprising the conoid, apical polar ring (APR), and preconoidal rings-assembles with precise spatiotemporal coordination to form functional daughter buds. Despite their essential roles in invasion, motility, and division, the scaffolding proteins orchestrating this ordered assembly have remained largely unidentified. Here, we identify and characterize RCC1-2 and APR8 as essential factors directing distinct, sequential phases of daughter cell apical complex construction. Both proteins are recruited with precise spatial and temporal dynamics to the daughter buds, where they function as scaffolds rather than static structural components. APR8 transiently occupies the basal region of the APR specifically in early daughter cells. It is dispensable for conoid and PCR initiation, yet its loss causes APR collapse, abolishes SPMT anchoring, and eventually arrests conoid maturation. In contrast, RCC1-2 localizes beneath the APR basal layer and persists throughout daughter cell development, where it contributes to stabilizing the attachment of SPMTs to the APR. Notably, in situ cryo-electron tomography further reveals that the interspersed pillars bridging SPMTs ends to the APR fail to form properly in RCC1-2-depleted parasites. These findings map a hierarchical RCC1-2/APR8-dependent scaffolding process that advances our understanding of parasite replication.
    DOI:  https://doi.org/10.64898/2026.02.13.705759
  5. Vet Anim Sci. 2026 Jun;32 100592
    Comparison of two DNA extraction methods for the detection of zoonotic protozoan pathogens in oysters and seawater.
    Veronica Rodriguez Fernandez, Minji Kim, Karen Shapiro.
      We compared freeze-thaw and bead beating methods for extracting DNA from parasites in oysters and seawater. Bead beating performed better for extracting Cryptosporidium, Giardia, and Toxoplasma in seawater, while freeze-thaw yielded comparable or better detection for Cryptosporidium and Giardia in oysters. This comparison highlights relative strengths and limitations of these methods.
    Keywords:  Cryptosporidium parvum; Extraction; Freeze-thaw; Giardia duodenalis; PCR; Shellfish; Toxoplasma gondii; bead beating; qPCR
    DOI:  https://doi.org/10.1016/j.vas.2026.100592
  6. BMC Genomics. 2026 Feb 27.
    Genome-wide transcriptomic analysis of Toxoplasma gondii reveals stage-specific regulatory programs and metabolic adaptations driving oocyst sporulation.
    Electine Magoye, Marc W Schmid, Chandra Ramakrishnan, Adrian B Hehl.
      
    Keywords:   Toxoplasma ; AP2; Gene-expression; Life-cycle; Pathways; RNA-seq; Sporozoite; Sporulation; Transcriptome; UMAP-HDBSCAN
    DOI:  https://doi.org/10.1186/s12864-025-12457-1
  7. Trends Parasitol. 2026 Feb 24. pii: S1471-4922(26)00035-8. [Epub ahead of print]
    Shifting metabolism alters rRNA expression in malaria parasites.
    Evi Hadjimichael, Kirk W Deitsch.
      Malaria parasites display the unique property of expressing distinct ribosomal RNAs at different points in their transmission cycle. Couble et al. determined that derepression of the mosquito-specific rDNA loci is initiated by altered NAD+/nicotinamide (NAM) ratios, resulting from the metabolic shift that parasites undergo as they transition into the mosquito stages.
    Keywords:  Silent Information Regulator 2 (Sir2); glycolysis; histone deacetylase; oxidative phosphorylation; ribosomal RNA
    DOI:  https://doi.org/10.1016/j.pt.2026.01.014
  8. Parasit Vectors. 2026 Feb 26.
    The effect of Toxoplasma gondii infection in parental male mice on the transcriptome of their offspring's brain.
    Ya-Nan Li, Hang Sun, Jian Ma, Xin-Yuan Zhou, Xiao-Man Xie, Huan-Huan Xie, Yan-Han Hou, Hong-Jie Dong, Gui-Hua Zhao, Chao Xu, Hong-Tao Li, Kun Yin.
       BACKGROUND: To investigate the mechanisms and intergenerational effects of Toxoplasma gondii infection in parental male mice on the transcriptome of the brain of their offspring.
    METHODS: Male parental mice were infected with the T. gondii strain TgCtwh6 and then mated with healthy female mice to produce offspring F1. Three independent and comparable groups were established: infected male mice (M) versus F1 male generation (F1♂) (M vs. F1♂), healthy female mice (F) versus F1 female generation (F1♀) (F vs. F1♀), and parental generation (P) versus F1 generation (F1) (P vs. F1). RNA was extracted from the brain tissues of both parental and offspring mice for transcriptome sequencing, screening for differentially expressed genes (DEGs) common to all three groups. DEGs were identified and validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, functional analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and evolutionary genealogy of genes: Nonsupervised Orthologous Groups (eggNOG) classification were performed to reveal the potential functions of DEGs in mice and genes in biological processes, key metabolic or signaling pathways, which provide a molecular basis for further studies on how to affect transcriptional expression in offspring.
    RESULTS: An overlap in gene expression was observed among the M versus F1♂, F versus F1♀, and P versus F1 comparisons. Collectively, these three comparisons identified 66 DEGs that were consistently altered across all groups, comprising 19 upregulated and 47 downregulated genes. GO analysis revealed that these DEGs were predominantly enriched in categories such as identical protein binding, positive regulation of NF-kappa B transcription factor activity, and membrane raft. KEGG analysis further indicated that the majority of enriched pathways were associated with immune responses, including those involved in viral infection pathways. qRT-PCR was employed to validate the expression changes of key genes.
    CONCLUSIONS: T. gondii infection of male parental mice significantly downregulates gene expression in the brain tissue of their offspring and negatively regulates the immune system and signal transduction pathways. This study provides valuable insights into the intergenerational effects of T. gondii infection and highlights the importance of further research in this critical area.
    Keywords:   Toxoplasma gondii ; Brain tissue; Intergenerational effects; Transcriptome
    DOI:  https://doi.org/10.1186/s13071-026-07302-7
  9. Nat Commun. 2026 Feb 23.
    A protein adaptor mediating Ap4A-dependent control of protein acetylation.
    Liujuan Zheng, Megan K M Young, Wieland Steinchen, Zhiyong Guo, Ekaterina Jalomo-Khayrova, Bobby Xuanyu Liu, Fabiana Burchert, Patricia Bedrunka, Christopher-Nils Mais, Jan Pané-Farré, Mathias Girbig, Uwe Linne, Aude Trinquier, Aitao Li, Georg Hochberg, Johannes Freitag, Jue D Wang, Gert Bange.
      Reversible lysine acetylation is a highly conserved post-translational modification across all domains of life controlling diverse cellular processes such as metabolism and gene expression. However, the regulation of protein acetylation remains poorly understood. Here, we report a regulatory system in Bacillus subtilis that controls the activity of the histone deacetylase (HDAC)-like protein AcuC, which has multiple substrates including acetyl-CoA synthetase and translation elongation factor. We show that AcuC is inhibited via formation of a stable complex with the hitherto uncharacterized protein AcuB. We furthermore demonstrate that the alarmone diadenosine tetraphosphate (Ap4A) binds to the cystathionine beta-synthase (CBS) domain of AcuB, thereby stabilizing AcuB and further enhancing the inhibition of AcuC. In summary, this study identifies AcuB as an Ap4A regulated deacetylation inhibitor, revealing a uncharacterized molecular mechanism to control HDAC-like proteins. Thus, the alarmone Ap4A modulates protein (de)acetylation, pointing towards a regulatory network that connects stress response, protein acetylation, and acetyl-CoA biosynthesis.
    DOI:  https://doi.org/10.1038/s41467-026-70006-0
  10. bioRxiv. 2026 Feb 20. pii: 2026.02.19.706824. [Epub ahead of print]
    The promoter-poised Rpd3 HDAC complex orchestrates global chromatin reprogramming upon nutrient transition.
    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.
    DOI:  https://doi.org/10.64898/2026.02.19.706824
  11. Nat Commun. 2026 Feb 21. pii: 1985. [Epub ahead of print]17(1):
    Non-hydrolyzable acetyllysine analogs to study protein acetylation in vitro and in cells.
    Simon Maria Kienle, Matthias Sigg, Tobias Schneider, Katrin Stuber, Jan Lehmann, Jasmin Jansen, Florian Stengel, Andreas Marx, Michael Kovermann, Martin Scheffner.
      Lysine acetylation plays a prominent regulatory role in eukaryotic cells. Yet, determining the functional consequences of acetylation for a given protein represents a considerable challenge. For instance, lysine residues are subject to various posttranslational modifications, rendering interpretation of mutational studies difficult. The genetic code expansion technology enables site-specific incorporation of acetyllysine (AcK) into proteins, but the applicability of AcK is limited, as within cells, the acetyl group is removed by deacetylases. Here, we show that site-specific incorporation of the non-hydrolyzable AcK analog ketolysine (KeK) into ubiquitin closely resembles the structural and functional effects of AcK incorporation. Furthermore, AcK and KeK can be efficiently incorporated into the tumor suppressor p53 in cells. However, whereas AcK becomes deacetylated, KeK remains stable. Accordingly, incorporation of KeK, but not AcK, affects p53-mediated transcription. Thus, we propose that KeK is a well-suited AcK surrogate for studying acetylation of a given protein in cells.
    DOI:  https://doi.org/10.1038/s41467-026-69782-6
  12. Microb Cell. 2026 ;13 86-102
    Protein arginine methyltransferases in protozoan parasites: a new path for antiparasitic chemotherapy?
    Gustavo D Campagnaro, Sébastien Pomel.
      Protein arginine methyltransferases (PRMTs) catalyse the transference of methyl groups from S-adenosylmethionine to arginine residues in substrate proteins, a post-translational modification widespread among eukaryotes. The change in size and hydrophobicity of the methylated arginine residue impacts on how a protein interacts with other macromolecules and affects several cellular processes, including intracellular signaling, DNA replication and repair, and control of gene expression. As a result, PRMTs became attractive targets for chemotherapy, and several PRMT inhibitors are going through clinical trials for cancer treatment. In protozoan parasites, PRMTs play fundamental roles during development, stage differentiation and infection processes. We here review the activity and the relevance of PRMTs for the survival of pathogenic kinetoplastids, apicomplexans and amoebas, highlight differences observed between PRMTs expressed in these organisms and their mammalian orthologues, and suggest that these enzymes can be exploited to combat parasitic infections. We propose that the arsenal of inhibitors developed to target mammalian PRMTs could be reassigned to allow the identification of new scaffolds to be explored as antiparasitic agents, either as sole chemotherapy or by improving the effectiveness of current antiparasitic drugs.
    Keywords:  amoeba; antiparasitic chemotherapy; apicomplexan; arginine methyltransferase; kinetoplastid; protozoan parasites
    DOI:  https://doi.org/10.15698/mic2026.02.869
  13. Mol Biomed. 2026 Feb 26. pii: 15. [Epub ahead of print]7(1):
    Lactate metabolism and protein lactylation in cancer.
    Zhaoyun Liu, Aili Li, Ziyu Ma, Junzhu Wang, Xinyu Chen, Zhiwei Wang, Rong Fu.
      Lactylation is a recently identified post-translational modification that links cellular metabolism to gene regulation, playing pivotal roles in cancer development and the tumor microenvironment (TME). Derived from lactate produced by glycolysis and glutamine metabolism, lactylation occurs on both histone and non-histone proteins, modulating transcription, protein function, and cellular signaling. In tumors, lactylation contributes to proliferation, metastasis, therapy resistance, and immune evasion by influencing the function of Treg cells, macrophages, dendritic cells, and NK cells. Its dynamic regulation by "writers" (e.g., p300), "erasers" (e.g., Histone deacetylases (HDACs), Sirtuins3 (SIRT3)), and transporters (e.g., monocarboxylate transporters (MCT) 1/4) provides multiple intervention points for therapy. Preclinical studies demonstrate that targeting lactylation directly or indirectly-through LDH (lactate dehydrogenase) inhibition, MCT blockade, or modulation of lactyltransferases-enhances the efficacy of immune checkpoint inhibitors, Chimeric Antigen Receptor T (CAR-T) therapy, and chemotherapeutic agents.Despite these advances, critical questions remain regarding the specificity of lactylation compared with other post-translational modifications, the tumor types most dependent on lactylation, and reliable biomarkers to guide treatment. Additionally, clinical validation of lactylation-targeting strategies is limited. Future research integrating mechanistic studies, patient-derived samples, and multi-omics approaches is essential to elucidate context-dependent functions, refine therapeutic targets, and develop precision interventions.This review provides a comprehensive summary of lactylation biology in cancer, highlighting its metabolic-epigenetic interplay, immunomodulatory roles, and therapeutic potential. By synthesizing current evidence, we aim to guide future studies and clinical strategies targeting lactylation to improve cancer treatment outcomes.
    Keywords:  Cancer therapy; Histone modification; Immune evasion; LDH; Lactylation; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s43556-026-00417-4
  14. bioRxiv. 2026 Feb 14. pii: 2026.02.13.705749. [Epub ahead of print]
    Tubulin acetylation governs organelle remodeling and lysosomal reformation during neuronal differentiation.
    Chih-Hsuan Hsu, Alexander Josiah Kinrade, Maria Clara Zanellati, Sarah Cohen.
      A functional nervous system depends on neuronal morphology established during differentiation. The microtubule (MT) cytoskeleton supports neuronal differentiation by organizing organelle positioning and facilitating transport. The dynamics and properties of MTs are regulated by a variety of post-translational modifications (PTMs), with many organelle interactions occurring preferentially on modified MTs. Here we find that tubulin acetylation is enriched at specific subcellular locations during differentiation of human induced neurons. We apply a quantitative multispectral imaging pipeline to simultaneously analyze eight membrane-bound organelles and define how tubulin acetylation reshapes organelle architecture and interaction networks during neuronal differentiation. We find that loss of tubulin acetylation broadly alters organelle morphology, spatial distribution, and inter-organelle interactions, with lysosome-organelle interactions most affected. Loss of acetylated MTs leads to enlarged, highly acidified lysosomes, impaired lysosomal fission, and accumulation of autolysosomes, consistent with defective lysosomal reformation. Super-resolution microscopy further reveals that lysosome-endoplasmic reticulum (ER) contacts preferentially associate with acetylated MTs. Together, our data support a model in which tubulin acetylation coordinates lysosome-ER interactions to facilitate lysosome remodeling and turnover. This work establishes tubulin acetylation as a key cytoskeletal regulator that links organelle interactions to organelle homeostasis important for neuronal differentiation.
    DOI:  https://doi.org/10.64898/2026.02.13.705749
  15. Nat Commun. 2026 Feb 26. pii: 1598. [Epub ahead of print]17(1):
    Plasmodium ARK1 regulates spindle formation during atypical mitosis and forms a divergent chromosomal passenger complex.
    Annu Nagar, Ryuji Yanase, Mohammad Zeeshan, David J P Ferguson, Steven Abel, Sarah L Pashley, Akancha Mishra, Anthonius Eze, Edward Rea, Declan Brady, Andrew R Bottrill, Sue Vaughan, Karine G Le Roch, David S Guttery, Anthony A Holder, Eelco C Tromer, Pushkar Sharma, Rita Tewari.
      Mitosis in Plasmodium spp., the causative agent of malaria, is fundamentally different from model eukaryotes, proceeding via a bipartite microtubule organising centre (MTOC) and lacking canonical regulators such as Polo kinases. During schizogony, asynchronous nuclear replication produces a multinucleate schizont, while rapid male gametogony generates an octaploid nucleus before gamete formation. Here, we identify Aurora-related kinase 1 (ARK1) as a key component of inner MTOC and spindle formation, controlling kinetochore dynamics and driving mitotic progression. Conditional ARK1 depletion disrupts spindle biogenesis, kinetochore segregation, karyokinesis and cytokinesis in both stages, and affects parasite transmission. Interactome analysis shows that ARK1 forms the catalytic core of a non-canonical chromosomal passenger complex (CPC) containing two highly divergent inner centromere proteins (INCENPs), which we term INCENP-A and INCENP-B, and lacking the canonical chromatin-targeting subunits Survivin and Borealin. Comparative genomics suggests that apicomplexan INCENPs arose through recurrent lineage-specific duplications, reflecting an evolutionary rewiring of CPC architecture in this eukaryotic lineage. Together, these findings reveal key adaptations in Plasmodium mitosis involving ARK1 and its INCENP scaffolds, and identify the ARK1-INCENP interface as a potential multistage target for antimalarial intervention.
    DOI:  https://doi.org/10.1038/s41467-026-69460-7
  16. J Cell Sci. 2026 Feb 27. pii: jcs.264392. [Epub ahead of print]
    UIP4 governs nuclear shape by modulating Saccharomyces cerevisiae lipidome.
    Pallavi Deolal, Bhaskar Das, Kathirvel Ramalingam, Amarthya Siddhartha, Reema Sahu, Krishnaveni Mishra.
      Cell survival under nutrient stress requires coordinated changes in metabolism and organelle function, yet the molecular mechanisms governing these adaptations remain poorly understood. In budding yeast, the protein Uip4 regulates nuclear morphology during the stationary phase, but its regulation and broader cellular roles are unknown. Here, we investigated how Uip4 expression is controlled and its effects on cellular homeostasis. We found that Uip4 expression is regulated by the transcription factor Msn2, downstream of Sch9 signalling, and responds to nutrient availability and energy state. Cells lacking Uip4 show poor stationary phase survival, dysregulated lipid profiles, and aberrant organelle morphology. These defects are rescued by overexpressing the lipin Pah1, indicating Uip4 functions in lipid homeostasis. Our findings reveal that such mechanisms linking nutrient signalling to lipid metabolism and organelle architecture are conserved, with implications for understanding cellular stress responses from yeast to humans.
    Keywords:  Lipid droplets; Mitochondria; Organelle contact; Stationary phase; Yeast
    DOI:  https://doi.org/10.1242/jcs.264392
  17. PLoS One. 2026 ;21(2): e0329048
    The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.
    Hernán A Tirado, Nithya Balasundaram, Jean Jacobs, Fleur Leguay, Lotfi Laaouimir, Nick van Gastel.
      Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic stem and progenitor cells characterized by profound metabolic dysregulation. Pyrimidine biosynthesis has emerged as a critical metabolic dependency in AML, but clinical translation has been hampered by unacceptable toxicity of current pyrimidine synthesis inhibitors. Since aspartate is an essential nutrient for pyrimidine biosynthesis, we investigated the role of aspartate import via the excitatory amino acid transporter 1 (EAAT1) in AML. We found that EAAT1 is broadly expressed across AML cell lines and patient samples, with enrichment in M4 and M5 subtypes and increasing levels following chemotherapy treatment. Pharmacological inhibition of EAAT1 impaired AML cell viability in vitro, but metabolomic profiling and nutrient rescue experiments showed that these effects were independent of intracellular aspartate levels. Moreover, AML cells cultured in aspartate-free medium maintained proliferation and did not become more sensitive to chemotherapy. EAAT1 inhibition in mice increased bone marrow plasma aspartate levels, confirming inhibition of cellular aspartate uptake, but did not affect growth or chemosensitivity of MLL-AF9-expressing AML cells in vivo. These findings suggest that AML cells possess several complementary mechanisms to support their aspartate requirements and that EAAT1 inhibition does not impair AML growth or response to chemotherapy.
    DOI:  https://doi.org/10.1371/journal.pone.0329048
  18. Cell Discov. 2026 Feb 24. pii: 13. [Epub ahead of print]12(1):
    ASCT2 palmitoylation regulated by JNK1-ZDHHC14 axis orchestrates glutamine metabolism and NSCLC progression.
    Xingyu Chen, Zihao Ke, Shihui Wei, Jiajin Chen, Ke Zhu, Jiaqi Xu, Yun Zhao, Mengyuan Cen, Yan Jin, Zhilei Pan, Juan Xiong, Ying Chen, Chenfang Dong, Qianhua Cao, Chao Cao.
      S-palmitoylation, a reversible post-translational modification regulates protein stability and cellular functions, yet its role in glutamine metabolism remains unclear. Here, we show that ZDHHC14 as the key palmitoyltransferase catalyzing ASCT2 palmitoylation at conserved Cys39 and Cys48 residues, promoting lysosomal degradation of this glutamine transporter, whereas ABHD17B functions as a depalmitoylase to stabilize ASCT2. Mechanistically, glutamine deprivation activates JNK1, which directly phosphorylates ZDHHC14 at Thr440 residue, triggering its degradation and thereby enhancing ASCT2 stability. Importantly, combination of JNK and ASCT2 inhibitors synergistically inhibits glutamine metabolism and tumor growth in vivo. These findings reveal a phosphorylation-palmitoylation axis linking JNK-mediated ASCT2 palmitoylation and glutamine metabolism, offering a potential therapeutic strategy for non-small cell lung cancer.
    DOI:  https://doi.org/10.1038/s41421-026-00870-z
  19. bioRxiv. 2026 Feb 11. pii: 2026.01.14.699600. [Epub ahead of print]
    Metabolic plasticity of sphingolipids governs cancer cell fitness in acidic tumor ecosystems.
    Raafat Chalar, Naheel Khatri, Jowana Obeid, Emma Downey, Joon-Hyun Song, Yujie Xiao, Saiful Samad, Andrew Chen, Andrew E Resnick, Khadijeh Karbalaei, Janet Allopenna, Cungui Mao, Christopher J Clarke, Fabiola Velazquez, Chiara Luberto, Bo Chen, Daniel Canals, Yusuf A Hannun, Mehdi Damaghi.
      Cancer cells must adapt to harsh tumor microenvironments, including acidic stress, to survive and thrive. Understanding how cancer cells achieve this adaptation can uncover new biomarkers and therapeutic strategies. In this study, we investigated the spatial metabolic phenotypic heterogeneity of breast cancer cells in acidic habitats using spatial multi-omics approaches on 3D spheroids. We found that cancer cells dynamically regulate sphingolipid metabolism to fine-tune their cell state to cope with acidic selection pressures. Cancer cells evolve mechanisms to deal with initially accumulating toxic ceramides but later adapt to it by rerouting SL metabolic pathways to eliminate them. Using advanced MALDI image analysis, and SL inhibitors on patient derived organoids, we demonstrated that cancer cells can switch between metabolic routes when key pathways are blocked, showcasing remarkable cell state plasticity. These insights highlight the potential to target metabolic plasticity as a novel therapeutic strategy to disrupt cancer adaptation and evolution, offering new avenues for cancer treatment.
    DOI:  https://doi.org/10.64898/2026.01.14.699600
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