bims-toxgon 2026-02-01 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2026–02–01
nineteen papers selected by
Lakesh Kumar, BITS Pilani

Transporters, an important but poorly studied area of Toxoplasma gondii.
A Spinster-like Transporter at the Inner Membrane Complex is critical for Toxoplasma gondii cytokinesis, motility and invasion.
Assessing the Toxoplasma Tachyzoite Cell Cycle Phases Using Fluorescent Ubiquitination-Based Cell Cycle Indicator.
Brain endothelial spheroids and cortical organoids reveal the impact of Toxoplasma gondii lineage and host-phagocyte-pathogen interactions on colonization.
Protection Against Toxoplasma gondii Lethal ME49 Challenge Induced by Influenza Virus-like Particles Containing Dense Granule Protein 14.
Babesia divergens host cell egress is mediated by essential and druggable kinases and proteases.
Exploring the Causal Links Between Toxoplasma gondii Infection and Risk of Brain Tumors: A Bidirectional Mendelian Randomization Analysis.
The deacetylase Sir2 is the primary sensor driving transcriptional changes in response to low NAD+ in the yeast Kluyveromyces lactis.
Generation and Characterisation of Peptide-Based IgY Antibodies Against SRS29B Protein of Toxoplasma gondii.
Mitochondria and Epigenetic Regulation: Bidirectional Crosstalk and Emerging Mitochondria-Targeted Degron Tools.
Bradyzoite subtypes rule the crossroads of Toxoplasma development.
Transcriptomic response to different heme sources in Trypanosoma cruzi epimastigotes.
Emerging Roles of Tubulin Isoforms and Their Post-Translational Modifications in Microtubule-Based Transport and Cellular Functions.
Coordination of cell organelles to promote metabolon formation.
SIRT2-mediated deacetylation of LCK governs the magnitude of T cell receptor signaling.
A two-step model of cell cycle-linked metacyclogenesis in Trypanosoma cruzi.
Interplay between nuclear survivin and the PRC2 complex and its impact on H3k27Me3 directed transcriptional repression.
Natural Product Driven Activation of UCP1 and Tumor Metabolic Suppression: Integrating Thermogenic Nutrient Competition with Cancer Metabolic Reprogramming.
CK2-mediated HDAC5 shuttling regulates DNA end resection through Ku70 deacetylation.

Parasit Vectors. 2026 Jan 25. 19(1): 51

Transporters, an important but poorly studied area of Toxoplasma gondii.

Liya Wang, Yujuan Jing, Jichao Yang, Xuke Yang, Jiahui Qian, Rui Fang, Fuchun Jian, Longxian Zhang, Senyang Li.

  Membrane transporters play a vital role in the obligate intracellular parasite Toxoplasma gondii, mediating the acquisition of nutrients from host cells, the regulation of ion gradients, and the maintenance of metabolic homeostasis. Despite their central importance for parasite survival, pathogenesis, and drug resistance, the majority of T. gondii transporters remain poorly characterized. Key unresolved questions include the mechanisms underlying purine nucleotide transport across the plasma membrane and the import/export of metabolites for core pathways in the apicoplast (e.g., thiamine, isopentenyl diphosphate[IPP]/dimethylallyl diphosphate [DMAPP], and coproporphyrinogen III) and mitochondria (e.g., amino acids and cofactors). Recent advances in bioinformatics and CRISPR-based phenotypic screening have enabled systematic identification of transporter candidates. This review summarizes current knowledge of T. gondii transporters localized to the plasma membrane, apicoplast, mitochondria, endoplasmic reticulum, and Golgi apparatus, highlighting their roles in nutrient acquisition, metabolic crosstalk, and organellar function. Furthermore, we propose a screening strategy integrating transmembrane domain prediction, CRISPR phenotyping, and hyperLOPIT-based protein localization to prioritize uncharacterized transporters for functional study. These insights underscore the potential of transporters as therapeutic targets and provide a roadmap for future research into the physiology of T. gondii.

Keywords:   Toxoplasma gondii ; Host; Substrate; Transporters

DOI:  https://doi.org/10.1186/s13071-025-07216-w
PLoS Pathog. 2026 Jan 28. 22(1): e1013886

A Spinster-like Transporter at the Inner Membrane Complex is critical for Toxoplasma gondii cytokinesis, motility and invasion.

Syrian G Sanchez, Romuald Haase, David J Dubois, Margaux Héritier, Rachel Humann, Nicolas Hulo, Bohumil Maco, Isabel Meister, Leonardo Scapozza, Oscar Vadas, Dominique Soldati-Favre.

The Major Facilitator Superfamily (MFS) comprises a large and diverse group of membrane transport proteins involved in the translocation of metabolites across cellular membranes. The genome of Toxoplasma gondii encodes approximately 60 putative MFS transporters, yet the functions of most remain poorly characterized. Conserved across the superphylum Alveolata, the inner membrane complex (IMC) is a specialized peripheral membrane system essential for parasite replication, structural integrity, motility, and host cell invasion. Here, we identify Toxoplasma gondii Daughter Cell Transporter 1 (TgDCT1), a previously uncharacterized MFS transporter, as a critical regulator of daughter cell formation. TgDCT1 localizes predominantly to the daughter cell IMC and contains a predicted spinster-like MFS domain. Phylogenetic and structural analyses reveal that TgDCT1 is conserved across Alveolata, shares a canonical MFS fold with its Plasmodium falciparum orthologue, and exhibits striking structural similarity to the human sphingosine-1-phosphate (S1P) transporter SPNS2, suggesting an evolutionarily conserved role in lipid transport. Conditional depletion of TgDCT1 results in severe defects in cytokinesis, including disrupted IMC architecture, aberrant daughter cell morphology, and failure of plasma membrane abscission. Although TgDCT1-depleted parasites retain the capacity for microneme secretion and egress, they display profoundly impaired motility and host cell invasion, ultimately leading to arrest of the lytic cycle. Notably, pharmacological inhibition of the S1P transporter SPNS2 using the compounds 11i and 33p phenocopies TgDCT1 depletion, impairing parasite morphogenesis, intracellular replication, and division synchrony. Furthermore, transgenic complementation demonstrates that the spinster-like domain of the P. falciparum DCT1 orthologue can functionally substitute for TgDCT1, indicating that these transporters likely recognize the same substrate. Together, these findings establish TgDCT1 as a central regulator of lipid homeostasis required for IMC maturation, endodyogeny, and parasite propagation in Toxoplasma gondii and likely other Apicomplexa.

DOI: https://doi.org/10.1371/journal.ppat.1013886
Bio Protoc. 2026 Jan 20. 16(2): e5588

Assessing the Toxoplasma Tachyzoite Cell Cycle Phases Using Fluorescent Ubiquitination-Based Cell Cycle Indicator.

Mrinalini Batra, Elena S Suvorova.

  Toxoplasma gondii is an apicomplexan parasite that infects a wide variety of eukaryotic hosts and causes toxoplasmosis. The cell cycle of T. gondii exhibits a distinct architecture and regulation that differ significantly from those observed in well-studied eukaryotic models. To better understand the tachyzoite cell cycle, we developed a fluorescent ubiquitination-based cell cycle indicator (FUCCI) system that enables real-time visualization and quantitative assessment of the different cell cycle phases via immunofluorescence microscopy. Quantitative immunofluorescence and live-cell imaging of the ToxoFUCCIS probe with specific cell cycle markers revealed substantial overlap between cell cycle phases S, G2, mitosis, and cytokinesis, further confirming the intricacy of the apicomplexan cell cycle. Key features • This protocol describes the development of the transgenic lines capable of detecting individual cell cycle phases and processes of the Toxoplasma tachyzoite cell cycle. • Quantitative immunofluorescence analysis and real-time microscopy enable the measurement of each cell cycle phase. • The ToxoFUCCIS probe helps to gain new insights into the highly flexible, overlapping nature of cell cycle organization in apicomplexan parasites.

Keywords:  Apicomplexa; Cell cycle; FUCCI; PCNA1; Toxoplasma gondii

DOI:  https://doi.org/10.21769/BioProtoc.5588
Cell Mol Life Sci. 2026 Jan 29.

Brain endothelial spheroids and cortical organoids reveal the impact of Toxoplasma gondii lineage and host-phagocyte-pathogen interactions on colonization.

Matias E Rodriguez, Elena Afanaseva, Ali Hassan, Felix Harryson-Oliveberg, Antonio Barragan.

  Toxoplasma gondii chronically infects the central nervous system (CNS), but the mechanisms enabling its traversal of the blood-brain barrier (BBB) remain unclear. Here, we investigated BBB penetration using brain endothelial spheroids and cerebral tissue-derived organoids that recapitulate three-dimensional barrier features. We show that T. gondii tachyzoites efficiently colonize spheroids, without detectable barrier disruption or obligatory parasite replication. Following direct transmigration, tachyzoites invaded and replicated within deeper cell layers. Type I strains (RH, CPS) exhibited higher colonization efficiency than type II strains (PRU, ME49), independent of replication. In contrast, when spheroids were exposed to T. gondii-infected dendritic cells (DCs), both strain types were transported similarly into deep cellular layers. Infected DCs adopted an amoeboid-like migratory phenotype that facilitated parasite transport and subsequent dissemination after egress. Colonization was attenuated by ICAM-1 blockade or heparin treatment, while the parasite effector GRA15, despite modulating DC-endothelial adhesion, did not significantly impact intratissue migration. In contrast, deletion of the effector TgWIP markedly reduced the number of infected DCs entering the spheroids. Similar colonization dynamics were observed in murine cerebral organoids. Collectively, these findings highlight spheroid and organoid models as robust systems for uncovering the cellular and molecular mechanisms underlying T. gondii BBB traversal and CNS colonization.

Keywords:  (MeSH): Three-dimensional cell culture; Blood-brain barrier, leukocyte migration; Central nervous system protozoal infections; Host-pathogen; Intracellular parasitism

DOI:  https://doi.org/10.1007/s00018-025-06035-7
Pharmaceutics. 2026 Jan 10. pii: 93. [Epub ahead of print]18(1):

Protection Against Toxoplasma gondii Lethal ME49 Challenge Induced by Influenza Virus-like Particles Containing Dense Granule Protein 14.

Jie Mao, Hae-Ji Kang, Gi-Deok Eom, Su In Heo, Hynnu Nam, Ji-Hyun Lee, Ki-Ho Park, Mi Suk Lee, Sung Soo Kim, Fu-Shi Quan.

  Background/Objectives: Toxoplasma gondii (T. gondii) dense granule antigen 14 (GRA14) is a parasitophorous vacuole membrane protein that plays a critical role in the development of chronic-stage cysts. However, its potential as a vaccine antigen and long-term immunity have not been evaluated using a virus-like particle (VLP) platform. Methods: influenza matrix protein (M1)-based VLPs displaying GRA14 were generated. Female BALB/c mice were intranasally immunized with the VLP vaccine and orally challenged with lethal ME49 cysts either 10 weeks or 32 weeks after prime vaccination for short-term and long-term immunity evaluation, respectively. Results: GRA14 VLP vaccination elicited higher levels of T. gondii-specific IgG, IgG1, and IgG2a antibody responses in sera compared to non-immunized controls. Upon challenge infection, elevated IgG- and IgA-secreting plasma cells, germinal center B cells, and memory B cells were observed, and CD4+, CD8+ T-cells, as well as both Th1 (IFN-γ) and Th2 (IL-4, IL-5) cytokines, were also increased. For the short-term immunity study, vaccinated mice exhibited suppressed cerebral inflammation, significantly reduced brain cyst burdens, maintained stable body weight, and achieved 100% survival. For the long-term study, GRA14 VLPs sustained elevated IgG and IgG1 levels as well as conferred partial yet significant protection, with lower cyst loads and 83% survival. Conclusions: GRA14 VLPs induce durable, balanced humoral and cellular immunity and provide both short-term and long-term protection against lethal chronic toxoplasmosis, supporting their potential as promising vaccine candidates.

Keywords:  GRA14; Toxoplasma gondii; protection; vaccine; virus-like particles

DOI:  https://doi.org/10.3390/pharmaceutics18010093
Nat Microbiol. 2026 Jan 27.

Babesia divergens host cell egress is mediated by essential and druggable kinases and proteases.

Brendan Elsworth, Caroline D Keroack, Yasaman Rezvani, Aditya S Paul, Keare A Barazorda, Niel C Bauer, Jacob A Tennessen, Samantha A Sack, Cristina K Moreira, Marc-Jan Gubbels, Marvin J Meyers, Kourosh Zarringhalam, Manoj T Duraisingh.

Egress from host cells is fundamental for the spread of infection by apicomplexan parasites, including Babesia species. These tick-borne pathogens represent emerging zoonoses, but treatment options are limited. Here, using microscopy, transcriptomics and chemical genetics, we identified signalling, proteases and gliding motility as key drivers of egress by Babesia divergens. We developed reverse genetic tools in B. divergens to perform a knockdown screen of putative mediators of egress, identifying kinases and proteases involved in distinct steps of egress (aspartyl protease (ASP) 3 and kinases cGMP-dependent protein kinase (PKG) and calcium-dependent protein kinase (CDPK4)) and invasion (ASP2, ASP3 and PKG) of red blood cells. Inhibition of egress stimulates additional rounds of intracellular replication, indicating that exit from the replication cycle is uncoupled from egress. Chemical genetics validated PKG, CDPK4, ASP2 and ASP3 as druggable targets in Babesia spp. and identified promising compounds for babesiosis treatment. Taken together, egress in B. divergens more closely resembles egress in Toxoplasma gondii than in the more evolutionarily related Plasmodium spp.

DOI: https://doi.org/10.1038/s41564-025-02238-7
Brain Behav. 2026 Feb;16(2): e71239

Exploring the Causal Links Between Toxoplasma gondii Infection and Risk of Brain Tumors: A Bidirectional Mendelian Randomization Analysis.

Pengqiang Shi, Gangao Wei, Zhenwei Li, Baoshun Du, Guodong Zhang, Jiaqi Zhang, Yungang Wang, Yunchao Chen, Zhang Cheng, Zhenguo Cheng.

   BACKGROUND: Toxoplasma gondii (T. gondii) is a ubiquitous protozoan parasite capable of establishing lifelong latent infections in the central nervous system. Previous epidemiological studies have suggested a potential association between T. gondii infection and an increased risk of brain cancer, but the causal relationship remains unclear.
METHODS: We conducted a bidirectional Mendelian randomization (MR) study to assess the causal relationship between T. gondii infection and brain tumor risk. Genetic instruments for T. gondii seropositivity were derived from a genome-wide association study (GWAS) in the UK Biobank, while genetic data for brain tumors were obtained from the FinnGen R12 dataset. Standard MR methods, including inverse-variance weighted (IVW), weighted median, and MR-Egger, were applied to infer causality, with generalized summary Mendelian randomization (GSMR) used for further validation. Sensitivity analyses, including heterogeneity and pleiotropy assessments, were performed to ensure robustness. Additionally, reverse MR analyses were conducted to evaluate whether brain tumors influence genetic liability to T. gondii seropositivity.
RESULTS: Our MR analyses found no evidence of a causal relationship between genetic liability to T. gondii seropositivity, as indicated by P22 and SAG1 antibody levels, and the risk of brain tumors. Across all tumor subtypes, IVW, weighted median, MR-Egger, and GSMR analyses consistently yielded non-significant results. However, reverse MR analysis suggested that genetic liability to malignant brain tumors is associated with increased odds of T. gondii seropositivity. For P22, a strong association was observed across methods (IVW: OR = 1.234, p = 0.004; GSMR: OR = 1.228, p = 0.006). In contrast, for SAG1 the evidence was weaker, with IVW indicating a suggestive association (OR = 1.094, p = 0.048) and GSMR showing a borderline association (OR = 1.088, p = 0.052). Sensitivity analyses confirmed the robustness of these findings, with no evidence of heterogeneity or pleiotropy. No significant associations were observed for meningioma, glioblastoma, or benign brain tumors.
CONCLUSION: Our study provides no evidence for a causal relationship between genetic liability to T. gondii seropositivity and brain tumor risk. However, reverse MR suggests that genetic liability to malignant brain tumors may be associated with increased odds of T. gondii infection.

Keywords:  GSMR; MR; T. gondii; brain cancer

DOI:  https://doi.org/10.1002/brb3.71239
Genetics. 2026 Jan 29. pii: iyag025. [Epub ahead of print]

The deacetylase Sir2 is the primary sensor driving transcriptional changes in response to low NAD+ in the yeast Kluyveromyces lactis.

Mahasweta Acharjee, Kristen Humphrey, Vincent Lactaoen, Charikleia Karageorgiou, Bowen Liu, Omer Gokcumen, Laura N Rusche.

  The coenzyme NAD+ (nicotinamide adenine dinucleotide) is a critical electron carrier in central metabolism and is required for cellular health. Cells are proposed to monitor and respond to fluctuating intracellular NAD+ levels using sirtuin deacetylases as sensors because these enzymes require NAD+ for activity. We tested this hypothesis by examining how intracellular NAD+ levels affect Sir2-mediated repression of transcription in the yeast Kluyveromyces lactis. Because K. lactis cannot synthesize NAD+, we could create a gradient of intracellular NAD+ levels by growing cells in varying concentrations of the precursor nicotinic acid. We found that as NAD+ levels decreased, acetylation of histones at target promoters increased, as did expression of these genes. RNA-Seq analysis revealed that genes induced in low nicotinic acid include some that would restore NAD+ levels, such as the high-affinity nicotinic acid transporter TNA1, and some that would enable long term survival by promoting sporulation. Most genes induced in low nicotinic acid (99/112 or 88%) were also induced by the deletion of SIR2. Moreover, in sir2Δ cells, few transcriptional changes occurred in response to low nicotinic acid. Thus, Sir2 is the primary sensor driving the transcriptional response to low NAD+ in K. lactis. Finally, the degree of transcriptional induction varied with NAD+ levels, suggesting that Sir2 behaves as a rheostat that tunes gene expression to NAD+ availability.

Keywords:   Kluyveromyces ; Keywords: sirtuin; NAD+; Sum1; deacetylase; niacin; nicotinic acid; sporulation; yeast

DOI:  https://doi.org/10.1093/genetics/iyag025
Parasite Immunol. 2026 Feb;48(2): e70063

Generation and Characterisation of Peptide-Based IgY Antibodies Against SRS29B Protein of Toxoplasma gondii.

Lauren Cruz Samaca, Noraida Zerpa, Henry Bermúdez, Oriana Zerpa, Caridad Malavé.

  Toxoplasmosis, a worldwide zoonotic infection caused by the protozoan parasite Toxoplasma gondii, has the potential to cause severe illness in both humans and animals. In this study, we describe the production and characterisation of IgY polyclonal antibodies capable of specifically recognising the SRS29B surface protein from Toxoplasma gondii tachyzoites lysates. To this end, a series of bioinformatics tools were employed to predict potential SRS29B B-cell epitopes, including Antheprot, IEDB, BCPREDS, ABCpred and Bepipred. Four peptides were synthesised to generate IgY antibodies. The production of specific antibodies against the SRS29B peptide constructs was confirmed in experimental animals using ELISA and MABA assays. This outcome demonstrated a correlation between the predictive analysis and the response obtained in chickens. Antibodies targeting the peptide constructs containing the SRS29B sequences (217-229 aa, 238-253 aa and 259-274 aa) recognised molecules present in the tachyzoite lysates of T. gondii, as confirmed by western blot analysis. This specific recognition was further supported by the inhibition of tachyzoite protein recognition upon exposure to homologous peptides. These findings suggest that three selected peptide constructs are suitable for the development of an antigen-capture assay to facilitate the detection of T. gondii in raw milk as well as for diagnosing acute toxoplasmosis.

Keywords:   Toxoplasma gondii ; IgY antibodies; egg yolk antibodies; immunodetection; synthetic peptides

DOI:  https://doi.org/10.1111/pim.70063
Cells. 2026 Jan 06. pii: 95. [Epub ahead of print]15(2):

Mitochondria and Epigenetic Regulation: Bidirectional Crosstalk and Emerging Mitochondria-Targeted Degron Tools.

Yingwei Xu, Xiaokun Jian, Lei Shi, Lisa S Shock, Lanming Chen, Louise T Chow, Hengbin Wang.

  Mitochondria not only generate ATP and metabolites essential for nuclear and cytoplasmic processes but also actively shape nuclear epigenetic regulation. Conversely, the nucleus encodes most of the proteins required for mitochondrial functions, and intriguingly, certain nuclear-encoded epigenetic factors-such as DNA and histone modifiers-also localize to mitochondria, where they modulate mitochondria genome stability, gene expression, metabolic flux, and organelle integrity. This reciprocal interplay defines mitochondria as both a source and a target of epigenetic regulation, integrating energy metabolism with gene expression and cellular homeostasis. This review highlights emerging mechanisms that link mitochondrial metabolism to chromatin remodeling, DNA and histone modifications, and transcriptional control, as well as how nuclear epigenetic enzymes translocate into mitochondria and regulates their functions. We also briefly introduce recent methodological advances that enable spatially selective depletion of mitochondrial proteins, offering new tools to dissect this bidirectional communication. Together, these insights underscore mitochondria's central role as an energetic and epigenetic hub coordinating nuclear function, development, and disease.

Keywords:  epigenetics; gene expression; metabolism; mitochondria

DOI:  https://doi.org/10.3390/cells15020095
Nat Commun. 2026 Jan 24.

Bradyzoite subtypes rule the crossroads of Toxoplasma development.

Arzu Ulu, Sandeep Srivastava, Nala Kachour, Brandon H Le, Michael W White, Emma H Wilson.

Toxoplasmosis is a major risk to chronically infected individuals, especially those who become immunocompromised. Although one-third of the globe is infected with Toxoplasma, no treatments prevent or eliminate cysts in part due to limited understanding of bradyzoite biology. The cyst is central to Toxoplasmosis, as transition from bradyzoites to tachyzoites drive pathology. In this study, we aim to understand the biology of bradyzoites prior to recrudescence and the developmental pathways they initiate. Here, we discover ME49EW cysts from infected mice harbor multiple bradyzoite subtypes with distinct fates. Purified subtypes exhibit defined developmental pathways in animals and in primary astrocytes. Single-bradyzoite RNA-sequencing reveals five major subtypes within cysts. We further show that a crucial subtype in chronically infected mice is absent from a widely used in vitro model of bradyzoite development. Altogether, this work establishes new foundational principles of Toxoplasma cyst development and reactivation that operate during the intermediate life cycle of Toxoplasma.

DOI: https://doi.org/10.1038/s41467-026-68489-y
Microb Cell. 2026 ;13 13-27

Transcriptomic response to different heme sources in Trypanosoma cruzi epimastigotes.

Evelyn Tevere, María G Mediavilla, Cecilia B Di Capua, Marcelo L Merli, Carlos Robello, Luisa Berná, Julia A Cricco.

  Heme is an essential molecule for most organisms, yet some parasites, like Trypanosoma cruzi, the causative agent of Chagas disease, cannot synthesize it. These parasites must acquire heme from their hosts, making this process critical for their survival. In the midgut of the insect vector, T. cruzi epimastigotes are exposed to both hemoglobin (Hb) and free heme resulting from its degradation. Despite the importance of this nutrient, how different heme sources influence parasite gene expression remains poorly understood. Here, we showed that heme restitution either as hemin or Hb to heme-starved parasites induces an early and distinct transcriptional response in T. cruzi epimastigotes. Using RNA sequencing at 4- and 24-hours post-supplementation, we identified gene subsets commonly or uniquely regulated by each heme source, including genes putatively linked to heme acquisition and metabolism. The study includes the first focused characterization of CRAL/TRIO domain-containing protein (TcCRAL/TRIO), a novel heme-responsive hemoprotein. Our results provide a more detailed picture of T. cruzi biology and highlights heme acquisition as a promising point of vulnerability to control parasite proliferation.

Keywords:  Chagas disease; Trypanosoma cruzi; heme; hemoglobin; transcriptome

DOI:  https://doi.org/10.15698/mic2026.01.865
Biomolecules. 2026 Jan 04. pii: 81. [Epub ahead of print]16(1):

Emerging Roles of Tubulin Isoforms and Their Post-Translational Modifications in Microtubule-Based Transport and Cellular Functions.

Aishwarya R Nair, Nived Saroj, Ambarish Kunwar.

  Microtubules are hollow cylindrical polymers made up of tubulin. This heterodimeric protein, tubulin, exists in multiple forms: tubulin isotypes and tubulin isoforms. Distinct α- and β-tubulin genes give rise to tubulin isotypes, which differ in their amino acid sequences and cellular expression patterns. The tubulin post-translational modifications (PTMs) encode regulatory information within the microtubule lattice, modifying its biophysical characteristics and shaping interactions with motor proteins and microtubule-associated proteins. Different tubulin isotype compositions and post-translational modification patterns generate distinct tubulin isoforms. These isoforms are tissue-specific and regulate the functions of microtubules in specialized cells and cellular components such as cilia. Tubulin isoforms control cellular transport, regulate mechanosensitivity and shape the cytoskeleton, impacting the cellular functions and homeostasis. This review discusses the tubulin PTMs, including acetylation, methylation, palmitoylation, polyamination, glutamylation, glycylation, tyrosination, phosphorylation, SUMOylation, and ubiquitination, with emphasis on how isotype diversity and PTM-driven regulation together modulate microtubule behaviour, intracellular transport, and cellular functions.

Keywords:  microtubule; post-translational modifications; tubulin isoforms; tubulin isotypes

DOI:  https://doi.org/10.3390/biom16010081
Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2532504123

Coordination of cell organelles to promote metabolon formation.

Zhou Sha, Anthony M Pedley, Timothy D Iles, Shaoqing Zhang, Jack R Staub, Ruobo Zhou, Stephen J Benkovic.

  The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5'-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.

Keywords:  biomolecular condensates; cell metabolism; de novo purine biosynthesis; metabolon; purine

DOI:  https://doi.org/10.1073/pnas.2532504123
Nat Immunol. 2026 Jan 29.

SIRT2-mediated deacetylation of LCK governs the magnitude of T cell receptor signaling.

Imene Hamaidi, Pingyan Cheng, Soo Young Jun, Alak Manna, Min-Hsuan Wang, Anh Nguyen, Ismail Can, Min G Zhang, Odesha O Taylor, Luis Uriel Lopez Bailon, Bin Fang, Bradford Perez, Ben C Creelan, Andriy Marusyk, Dongjun Shin, Tae Hyun Hwang, Anders E Berglund, Virginia S Shapiro, Haitao M Ji, José R Conejo-Garcia, Sungjune Kim.

T cell receptor (TCR) signaling is precisely tuned to prevent self-reactivity while allowing protective immunity. Here we found that acetylation modulated TCR signaling. The loss of SIRT2 deacetylase activity in T cells led to amplified calcium mobilization and phosphorylation of key proximal TCR molecules in naive T cells and reversed dampened TCR signaling in anergic T cells. During thymic selection, SIRT2 deficiency lowered the TCR signaling threshold and resulted in a broader TCR repertoire diversity. Mechanistically, we identified acetyl-lysine K228 on the linker region of LCK as a substrate specific for SIRT2 that governed LCK conformation and activity. SIRT2 inhibition in exhausted mouse and human tumor-infiltrating T cells restored TCR responsiveness and antitumor immunity. These findings highlighted SIRT2-modulated protein acetylation as a regulatory mechanism that set the TCR threshold in T cells.

DOI: https://doi.org/10.1038/s41590-025-02377-3
Acta Trop. 2026 Jan 27. pii: S0001-706X(26)00031-8. [Epub ahead of print] 107997

A two-step model of cell cycle-linked metacyclogenesis in Trypanosoma cruzi.

Ana Paula De Jesus Menezes, Melissa Martins De Oliveira, Sergio Schenkman, Ariel Mariano Silber, Julia Pinheiro Chagas da Cunha, Maria Carolina Elias.

  The causative protozoan of Chagas disease, Trypanosoma cruzi, undergoes a complex life cycle involving cell cycle regulation and differentiation. However, the connection between these processes remains unclear. Here, we investigated the cell cycle phase in which commitment to metacyclogenesis occurs. Using synchronized populations, CFSE labeling, and cytokinesis inhibition, we show that differentiation stimuli can be perceived from G2/M to G1, but execution takes place exclusively in G1. CFSE results revealed that parasites already in G1 differentiate without division, whereas inhibition of cytokinesis assays demonstrated that post-G1 cells must complete cytokinesis before producing metacyclics. Together, these findings support a two-step model, stimulus perception followed by execution in G1, providing new insights into T. cruzi differentiation and advancing our understanding of parasite development and transmission.

Keywords:  Trypanosoma cruzi; cell cycle; metacyclogenesis

DOI:  https://doi.org/10.1016/j.actatropica.2026.107997
J Cell Sci. 2026 Jan 30. pii: jcs.264572. [Epub ahead of print]

Interplay between nuclear survivin and the PRC2 complex and its impact on H3k27Me3 directed transcriptional repression.

Adesh D Vaidya, Alexander J Fezovich, Sally P Wheatley.

  The PRC2 complex tri-methylates histone 3 at lysine 27 (k27), a post translational modification that induces heterochromatin formation and transcriptional repression. Survivin is a nucleocytoplasmic shuttling protein that is kept out of the nucleus in clement conditions, but that accumulates there in times of stress and in certain specialised cells. While the cytoplasmic functions of survivin are well documented, there is comparatively less understanding of its roles within the nucleus. Here we investigated whether nuclear survivin can affect transcriptional programming. Using interaction analyses and qPCR we report that it binds to the enzymatic subunit of the polycomb repressor complex 2, EZH2 and H3k27Me3, and causes depression of its target genes in a variety of human cells.

Keywords:  H3K27Me3; Hypoxia; Polycomb Repressor Complex 2; Stem cells; Survivin; Transcription

DOI:  https://doi.org/10.1242/jcs.264572
Biomolecules. 2026 Jan 06. pii: 90. [Epub ahead of print]16(1):

Natural Product Driven Activation of UCP1 and Tumor Metabolic Suppression: Integrating Thermogenic Nutrient Competition with Cancer Metabolic Reprogramming.

Dong Oh Moon.

  Metabolic reprogramming allows cancer cells to proliferate rapidly, survive nutrient limitation, and resist stress, making tumor metabolism an important therapeutic target. However, pharmacological inhibition of metabolic enzymes often causes systemic toxicity and compensatory pathway activation. To overcome these limitations, recent studies have highlighted an alternative host-centered strategy based on increasing systemic energy expenditure. Recent studies highlight an alternative strategy in which the host increases energy expenditure through uncoupling protein 1 (UCP1) dependent thermogenesis, thereby lowering systemic glucose, fatty acid, and nucleotide availability for tumors. Engineered beige adipocytes overexpressing UCP1, PR domain-containing protein 16 (PRDM16), or peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A/PGC1A) suppress tumor growth through nutrient competition, suggesting that activating endogenous UCP1 may provide a non-genetic and physiologically aligned anticancer approach. Building on this concept, natural products such as polyphenols, terpenoids, alkaloids, and carotenoids have emerged as promising UCP1 activators that stimulate beige and brown adipocyte thermogenesis through pathways involving AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), PGC1A, PRDM16, and mitochondrial biogenesis. In parallel, computational studies further indicate that several plant-derived compounds bind directly to the central cavity of UCP1 with high affinity, offering structural support for their thermogenic action. Importantly, many of these compounds also inhibit cancer cell intrinsic metabolism by reducing glycolysis, oxidative phosphorylation, lipid synthesis, and amino acid dependent anaplerosis. This review integrates UCP1 biology, natural product mediated thermogenesis, molecular docking evidence, and tumor metabolic suppression, proposing a unified framework in which natural compounds impose coordinated metabolic pressure on cancer through both adipocyte-driven nutrient competition and direct inhibition of tumor metabolism.

Keywords:  PRDM16; UCP1; natural products

DOI:  https://doi.org/10.3390/biom16010090
Theranostics. 2026 ;16(7): 3648-3664

CK2-mediated HDAC5 shuttling regulates DNA end resection through Ku70 deacetylation.

Xueyi Liang, Jingyuan Zhao, Shoukang Li, Ruozheng Wei, Haixin Yu, Qiyue Zhang, Qixun Fu, Gengdu Qin, Yuhan Zhao, Jiaying Liu, Zhiqiang Liu, Tao Peng, Junpeng Meng, Shanmiao Gou, Tao Yin, Heshui Wu, Bo Wang, Yingke Zhou.

  Rationale: Loss of histone deacetylase 5 (HDAC5) is frequently observed in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC), and is associated with poor patient survival. Although HDAC5 has been implicated in DNA damage repair, the molecular mechanisms by which it regulates DNA double-strand break (DSB) repair pathway choice remain unclear. Methods: Using PDAC cell lines, genetically engineered mouse models, patient-derived organoids, and biochemical assays, we investigated the role of HDAC5 in DNA end resection and homologous recombination (HR). Protein interactions, post-translational modifications, DNA repair pathway activity, and cellular responses to DNA damage and PARP inhibition were systematically analyzed. Results: We identify HDAC5 as a critical regulator of DNA end resection and HR through deacetylation of Ku70. DNA damage induces casein kinase 2 (CK2)-mediated phosphorylation of HDAC5, promoting its nuclear translocation. Nuclear HDAC5 directly deacetylates Ku70 at lysine 287, facilitating Ku70 dissociation from DSB sites, thereby enabling DNA end resection and HR repair. In contrast, HDAC5 loss or CK2 inhibition results in Ku70 K287 hyperacetylation, prolonged retention of the Ku heterodimer at DSBs, impaired DNA end resection, and suppression of HR. Consequently, HDAC5-deficient PDAC cells exhibit increased sensitivity to PARP inhibitors, while pharmacological CK2 inhibition sensitizes HDAC5-proficient tumors to PARP inhibition. Conclusions: These findings uncover a previously unrecognized CK2-HDAC5-Ku70 signaling axis that governs DNA repair pathway choice by regulating DNA end resection. Targeting this axis provides a mechanistic rationale for enhancing PARP inhibitor sensitivity in PDAC, including tumors without classical homologous recombination deficiency.

Keywords:  CK2; HDAC5; Ku70; PARP inhibitor; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.7150/thno.122935