bims-toxgon 2026-05-17 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2026–05–17
24 papers selected by
Lakesh Kumar, BITS Pilani

A two-membrane gateway for monocarboxylates couples host glycolysis to Toxoplasma mitochondrial fitness and virulence.
Toxoplasma IMC1 is a central component of the subpellicular network and plays critical roles in parasite morphology, replication, and infectivity.
Parasite-specific essential bromodomain protein TgBDP4 is a key epigenetic reader and a potential drug target for the parasite Toxoplasma gondii.
Harnessing Toxoplasma gondii microneme proteins for serodiagnosis and vaccine development: a review.
Two distinct SWI/SNF complexes direct chromatin-linked transcriptional programs in Toxoplasma.
Correction to "Generation and Characterisation of Peptide-Based IgY Antibodies Against SRS29B Protein of Toxoplasma gondii".
The Potential Function of Toxoplasma gondii in Tumour Immunotherapy.
The apical polar ring is essential during the blood stage of Plasmodium falciparum.
A bacterial-type cardiolipin synthase in Plasmodium spp. supports mitochondrial respiration and is important for liver stage maturation.
Toxoplasma gondii KCR is a Noncanonical Modulator of CSF2 Signaling that Targets the CSF2Rα-JAK2/STAT5 Axis.
Hierarchical small molecule inhibition of MYST acetyltransferases.
Composition and role of the vacuolar transporter chaperone complex in polyphosphate synthesis and infectivity in Trypanosoma cruzi.
Neutrophilic cholangitis associated with intracholangiocytic Hammondia protozoa confirmed in 2 dogs and suspected in 2 dogs.
Serial passage is associated with virulence attenuation in Neospora caninum and transcriptomic remodeling of invasion- and chronic-stage-associated pathways.
Insights into SIRT2 inhibition from machine learning-assisted multi-level screening of the NCI database.
Identification of the regulatory elements and protein substrates of lysine acetoacetylation.
Deciphering Membrane Pore Formation Mechanisms of Plasmodium falciparum Perforin-Like Protein 1 (PfPLP1).
Molecular mechanisms of SIRT1 in regulating ageing and related intervention strategies.
Mechanistic insights on spatiotemporal control of Ras-signaling.
Post-translational modifications as key regulators of proline metabolism.
HDAC11 Regulates RNA Splicing via De-Fatty Acylation of SF3B2.
Spatiotemporal dynamics of signal dependent exocytosis and parasitophorous vacuolar membrane rupture during Plasmodium falciparum egress.
Cross-kingdom communication between plants and parasitic nematodes.
Acetylated Vps1 initiates autophagy and regulates the sorting nexin dynamics essential for pathogenicity in fusarium graminearum.

bioRxiv. 2026 Feb 24. pii: 2026.02.23.707530. [Epub ahead of print]

A two-membrane gateway for monocarboxylates couples host glycolysis to Toxoplasma mitochondrial fitness and virulence.

Melanie Key, Steven Joseph, Zhicheng Dou.

Intracellular pathogens must coordinate their metabolism with nutrient supplies from the host cell, yet the specific metabolites and transport pathways that sustain parasite bioenergetics remain incompletely defined. In the apicomplexan parasite Toxoplasma gondii , infection increases host glycolytic flux and elevates cytosolic lactate and pyruvate, suggesting that these intermediates are co-opted as carbon and energy sources. Here, we show that T. gondii imports host-derived lactate and pyruvate across both the parasitophorous vacuole membrane and the parasite plasma membrane to maintain mitochondrial function, extracellular survival, and acute virulence. Using a hexokinase knockout (Δ hk ) to abolish endogenous pyruvate production, we find that parasites preserve basal oxygen consumption but become strictly dependent on exogenous monocarboxylates to stimulate mitochondrial respiration. By disrupting the parasite formate-nitrite transporters TgFNT1-3, we identify TgFNT1 and TgFNT2 as the principal monocarboxylate transporters required for lactate- and pyruvate-driven respiratory responses. Furthermore, genetic ablation of TgGRA17, a parasitophorous vacuole pore protein, compromises the growth advantage conferred by elevated exogenous lactate, implicating this pore as the entry route for host-derived monocarboxylates into the vacuole. Conversely, host cells lacking the monocarboxylate exporter MCT1 accumulate cytosolic lactate/pyruvate and enhance parasite growth, linking host monocarboxylate export to parasite fitness. When both endogenous pyruvate production and exogenous uptake are disrupted, parasites display severely reduced mitochondrial basal respiratory capacity, membrane potential, ATP levels, extracellular survival, and virulence in mice. Collectively, these findings define a dual-step pyruvate acquisition pathway in T. gondii and reveal host monocarboxylates as critical fuels that buffer parasite bioenergetic stress during infection.
Significance Statement: Intracellular parasites rely on host nutrients to power their metabolism, yet the routes by which these metabolites cross the membranes between host cytosol and parasite mitochondria are not well defined. Here, we show that Toxoplasma gondii exploits host glycolysis by importing lactate and pyruvate to sustain mitochondrial function and virulence. We identify a two-step pathway in which these monocarboxylates cross the parasitophorous vacuole via the pore GRA17 and then enter the parasite through the formate-nitrite transporters TgFNT1/2. Blocking both endogenous glycolysis and this exogenous pyruvate supply disables parasite mitochondrial fitness, extracellular survival, and virulence. These findings reveal a fundamental strategy of metabolic plasticity in apicomplexan parasites using a multi-membrane nutrient gateway that couples host glycolysis to parasite bioenergetics.

DOI: https://doi.org/10.64898/2026.02.23.707530
PLoS Pathog. 2026 May;22(5): e1014080

Toxoplasma IMC1 is a central component of the subpellicular network and plays critical roles in parasite morphology, replication, and infectivity.

Juliette N Uy, Qing Lou, Z Hong Zhou, Peter J Bradley.

Toxoplasma gondii and related apicomplexan parasites utilize a unique membrane and cytoskeletal organelle called the inner membrane complex (IMC) for maintaining cell shape, motility, host cell invasion, and replication. The cytoskeleton portion of the organelle is a network of filaments composed of proteins called alveolins, whose precise functions and organization are poorly understood. Here we describe the function of the founding member of the Toxoplasma alveolins, IMC1, which we show is expressed and loaded onto forming daughter buds with IMC4, but later than the other key alveolins IMC3, IMC6, and IMC10. Disruption of IMC1 results in severe morphological defects that impact the integrity of the parasite's cytoskeleton and disrupt invasion, replication, and egress. Loss of IMC1 in a less virulent type II strain results in a dramatic loss of infectivity and complete failure to form a chronic infection. We then use deletion analyses to dissect functional regions of the protein which reveals a key subregion of the alveolin domain that is sufficient for IMC targeting and also required for function. We then show that IMC1 interacts directly with IMC4 and the loss of IMC1 results in mislocalization of IMC4 specifically in forming daughter buds. This study thus reveals the critical role that IMC1 plays in forming and maintaining the architecture of the filamentous network of the IMC.

DOI: https://doi.org/10.1371/journal.ppat.1014080
J Biol Chem. 2026 May 14. pii: S0021-9258(26)02032-6. [Epub ahead of print] 113160

Parasite-specific essential bromodomain protein TgBDP4 is a key epigenetic reader and a potential drug target for the parasite Toxoplasma gondii.

Rajkumar Gurupwar, Chitti Raju Khandavalli, Abhijit S Deshmukh.

  Toxoplasma gondii, an apicomplexan parasite, relies heavily on epigenetic regulation of gene expression, which is controlled by chromatin-modifying enzymes and histone acetylation, to invade and establish infection in the host. Bromodomain proteins are important epigenetic regulators in parasites, acting as 'readers' of histone lysine acetylation to control gene expression. While many bromodomain proteins are unique to parasites, only a few have been explored for therapeutic applications. In this study, we characterized the parasite-specific bromodomain protein TgBDP4 as a key epigenetic reader and a potential drug target for toxoplasmosis. Protein-peptide interaction and pull-down studies reveal that TgBDP4 interacts strongly with acetylated histone H3 as well as unphosphorylated and Ser5-phosphorylated forms of RNA polymerase II-CTD, which are necessary for gene activation. Using a conditional knockdown approach, we demonstrate that TgBDP4 is essential for parasite survival in both cell culture and a mouse host. When the therapeutic potential of TgBDP4 was evaluated using three bromodomain inhibitors, I-BRD9, (+)-JQ1, and I-BET151, we found that I-BRD9, a selective inhibitor of HsBRD9, effectively inhibits TgBDP4 activity at much lower concentrations than HsBRD9. This inhibition occurs through the binding of I-BRD9 to conserved key residues of the acetyl-lysine-binding pocket of TgBDP4, resulting in a complete arrest of parasite replication in culture and extending the survival time of infected mice. Overall, this study highlights the indispensable role of TgBDP4-mediated gene regulation for parasite survival, establishing TgBDP4 as a promising drug target for treating toxoplasmosis.

Keywords:  Apicomplexa; BDP4; BET inhibitors: I-BRD9; Bromodomain protein; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.jbc.2026.113160
Ann Med. 2026 Dec;58(1): 2667678

Harnessing Toxoplasma gondii microneme proteins for serodiagnosis and vaccine development: a review.

Yanfei Ji, Zhihao Wang, Yuxuan Feng, Irfan Ahmad, Khalid J Alzahrani, Khalaf F Alsharif, Fuad M Alzahrani, Xia Zhao, Abdul Qadeer, Wenqiang Liu.

   INTRODUCTION: Toxoplasma gondii (T. gondii), an obligate intracellular apicomplexan parasite, infects virtually all warm-blooded animals through a sophisticated sequential invasion mechanism involving coordinated secretion from specialized apical organelles. Among these secretory proteins, microneme proteins (MICs) serve as central molecular effectors orchestrating host-parasite interactions. This review comprehensively examines the structural organization, regulatory mechanisms, and diverse functions of MICs in T. gondii pathogenesis, and evaluates their translational potential for diagnostics and vaccine development.
DISCUSSION: Key MIC adhesin complexes - including the lectin-based MIC1/4/6 complex and the transmembrane MIC2-M2AP complex - mediate glycan recognition, host cell attachment, moving junction formation, and gliding motility. Beyond invasion, MICs function as immunomodulators engaging Toll-like receptors (TLR2, TLR4, TLR11) to elicit pro-inflammatory responses while activating EGFR-Akt signaling to inhibit autophagy. The translational potential is substantial: MIC-based antigens enable sensitive serodiagnosis, differentiating acute from chronic infections. In contrast, MIC-based vaccines across multiple platforms demonstrate considerable protective efficacy in preclinical experimental models. Notably, the MIC1-3 knockout strain confers protection in sheep that is comparable to that of commercial vaccines; however, it is important to note that most supporting evidence remains at the preclinical stage and clinical validation in human populations is still required.
CONCLUSIONS: MICs represent promising targets that bridge fundamental parasitology and clinical applications. Integration of MIC biology with translational strategies provides foundations for developing next-generation diagnostics and vaccines against toxoplasmosis.

Keywords:  Toxoplasma gondii; host cell invasion; immunomodulation; microneme proteins; serodiagnosis; vaccine development

DOI:  https://doi.org/10.1080/07853890.2026.2667678
Nat Commun. 2026 May 15.

Two distinct SWI/SNF complexes direct chromatin-linked transcriptional programs in Toxoplasma.

Dominic Schwarz, Benicio Tapia, Sebastian Lourido.

Chromatin remodeling complexes dynamically modify DNA accessibility to regulate gene expression during eukaryotic cell cycle progression, developmental transitions, and environmental adaptation. Higher eukaryotes have multiple remodeler subtypes; however, the coordination and functional specificity of these diverse complexes is not well understood. Apicomplexan parasites such as Toxoplasma gondii have a limited set of chromatin remodelers offering a divergent setting in which to explore the function of homologous complexes. These parasites have retained the Myb domain-containing proteins with homology to chromatin-associated regulators like SNF2h and SWI3. Here, a comprehensive analysis of the Myb protein family in Toxoplasma defines the composition of two SWI3 complexes with mutually exclusive ATPase homologs-TgSNF2a and TgSNF2b. Integrating transcriptomics with a custom chromatin-profiling strategy, we show that TgSNF2a is essential for the timely transcription of genes, while TgSNF2b ensures global transcriptional competency throughout the cell cycle and developmental transitions. Cell cycle-resolved chromatin profiling conclusively shows the shift from TgSNF2b to TgSNF2a occupancy when regulated genes transition from being poised to being actively transcribed. Our findings demonstrate that TgSNF2a and TgSNF2b perform distinct yet interdependent regulatory roles shaped by their chromatin context. This work offers new insight into the functional diversification of SWI/SNF complexes across eukaryotes.

DOI: https://doi.org/10.1038/s41467-026-73079-z
Parasite Immunol. 2026 May;48(5): e70084

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

DOI: https://doi.org/10.1111/pim.70084
Immunology. 2026 May 10.

The Potential Function of Toxoplasma gondii in Tumour Immunotherapy.

Jiexing Tan, Zi-Guo Yuan, Luodan Yang, Changsheng He, Sha Wu, Wei Zhu, Li Gong.

  Immunotherapy has revolutionised the clinical treatment of many types of cancer, including immune checkpoint inhibitors, adoptive cell therapies, and tumour vaccines, which are capable of providing long-term clinical benefit in some patients. Nevertheless, a high degree of tumour immune heterogeneity and an ongoing immunosuppressive the tumour microenvironment (TME) remain as limitations to therapeutic outcomes, and alternative methods to stimulate antitumor immunity are necessary. Given these limitations, recent researchers has been attracted to the fact that Toxoplasma gondii and its derivatives can be considered as unconventional parasite-derived immunomodulatory vectors in cancer immunotherapy. T. gondii infection triggers strong Th1 immunity mediated on interleukin-12 (IL-12) and interferon-γ (IFN-γ), promotes dendritic cell maturation, and activates cytotoxic T cells, thus reprogramming the TME to a more immunostimulatory condition. Attenuated or metabolic-deficient strains have shown strong antitumor efficacy in various murine tumour models by reducing tumour burden and prolonging host survival. Meanwhile, the effector proteins of the parasite, such as GRA15, GRA16, and ROP18, regulate immune cell function to induce tumour cell apoptosis, inhibit angiogenesis, and suppress metastasis. The T. gondii-infected cell-derived exosomes and T. gondii lysate antigens are also immunogenic and represent safer, non-infectious therapeutic alternatives. Here, we summarise the latest advances in the antitumor effects of T. gondii and its derivatives, focusing on immune activation, signalling regulation, direct antitumor effects, synergistic immunotherapy, potential for drug development, and challenges in future clinical translation. T. gondii and its derivatives have shown the potential to reshape TME and convert 'cold' tumours into 'hot' ones in murine cancer models. We believe that with further research in this field, the future of cancer immunotherapy will see breakthrough advancements.

Keywords:  antitumor; cancer; immune response; parasite; tumour microenvironment

DOI:  https://doi.org/10.1111/imm.70147
Nat Microbiol. 2026 May 14.

The apical polar ring is essential during the blood stage of Plasmodium falciparum.

Pratima Gurung, Peter S Back, Ilzat Ali, Gabrielle M Hernandez, Jeffrey D Dvorin.

The apical polar ring (APR) is a defining cytoskeletal structure in apicomplexan parasites, critical for parasite morphology and host cell invasion. However, its molecular composition and function remain elusive in Plasmodium falciparum. Here we identify and characterize PfAPR3 as an APR-resident protein. Conditional knockout of PfAPR3 reveals its essential role in asexual replication. PfAPR3-knockout parasites contact host red blood cells but fail to form a tight junction, resulting in a complete block in invasion. Using PfAPR3 as bait, we identify three additional APR proteins (PfAPR4, PfCHAKRA and PfAPR5) and delineate APR biogenesis with ultrastructure expansion microscopy. Unlike PfAPR3, PfCHAKRA is critical for cytoskeletal network organization. Iterative ultrastructure expansion microscopy further shows PfCHAKRA at the basal APR until mid-schizogony, with PfAPR3 exhibiting dual apical-basal ring localization during schizogony. These findings define the molecular architecture and function of the APR in P. falciparum and have implications for understanding parasite host cell infection.

DOI: https://doi.org/10.1038/s41564-026-02365-9
PLoS Pathog. 2026 May;22(5): e1014215

A bacterial-type cardiolipin synthase in Plasmodium spp. supports mitochondrial respiration and is important for liver stage maturation.

Karavadra Asha Adhur, Nirdosh Nirdosh, Aakash Chandramouli, Swarnali Basu, Amit Lahiri, Siddhesh Shashikant Kamat, Satish Mishra, Saman Habib.

The mitochondrion of malaria-causing Plasmodium spp. supports parasite energy requirements, pyrimidine and ubiquinone biosynthesis and [Fe-S] formation. As parasites transition from the host liver to asexual and sexual blood stages, metabolic shifts of ATP generation through glycolysis or mitochondrial oxidative phosphorylation are accompanied by change in mitochondrial number, branching complexity and development of cristae. The final step of synthesis of cardiolipin (CL), a critical phospholipid for mitochondrial biogenesis and function, is catalyzed by cardiolipin synthase (Cls). Plasmodium spp. carry an uncharacterized, putative bacterial-type Cls distinct from Cls of mammalian hosts. We probed enzyme activity of the phospholipase D-type recombinant Plasmodium falciparum Cls. Antibodies generated against PfCls localized it to the mitochondrion in asexual blood stages; additional PfCls signal was observed in the cytosolic periphery in late-gametocytes, accompanied by CL staining in the parasite plasma membrane. To investigate the impact of Cls on parasite life cycle progression, we generated its knockout in the rodent parasite P. berghei. PbCls KO parasites had significantly impaired asexual blood-stage proliferation associated with lower abundance of CL molecular species. They showed a marked reduction in mitochondrial membrane potential and basal oxygen consumption rate. While PbCls-deficient parasites completed development within the mosquito and generated sporozoites capable of hepatocyte invasion, they exhibited a severe defect in liver-stage maturation. Plasmodium Cls is thus a vital component of malaria parasite development with a critical role in maintaining mitochondrial function.

DOI: https://doi.org/10.1371/journal.ppat.1014215
Transbound Emerg Dis. 2026 ;2026 8426765

Toxoplasma gondii KCR is a Noncanonical Modulator of CSF2 Signaling that Targets the CSF2Rα-JAK2/STAT5 Axis.

Jie Mei, Xianglin Pu, Mengkai Zhang, Yue Liu, Chuang Meng, Lixin Xu, Xiaokai Song, Ruofeng Yan, Xiangrui Li, Mingmin Lu.

  Toxoplasma gondii establishes infection in hosts by deploying effector proteins that reprogram cytokine-driven immunity. While protozoan parasite-encoded macrophage migration inhibitory factor (MIF) homologs exemplify cytokine mimicry, whether T. gondii targets additional host cytokine axes remains unclear. Here, we identify a T. gondii 3-ketoacyl-CoA reductase (KCR) as a noncanonical cytokine modulator that engages the granulocyte-macrophage colony-stimulating factor (CSF2) receptor alpha chain (CSF2Rα). In HEK293T cells, forward and reverse co-immunoprecipitation (Co-IP) assays demonstrated a specific interaction between KCR and murine CSF2Rα. The recombinant KCR triggered rapid activation of canonical CSF2 signaling in RAW264.7 macrophages, inducing phosphorylation of JAK2 and STAT5 to levels comparable to murine CSF2. Functionally, KCR enhanced NADPH oxidase-dependent oxidative responses, increasing intracellular reactive oxygen species (ROS) and upregulating transcripts encoding core oxidase subunits, including CYBB, CYBA, NCF1, and NCF2. KCR also promoted phagocytic capacity, elevating FITC-dextran uptake and inducing expression of complement, Fc, and scavenger receptor genes, including CR3, CD16, CD64, MSR1, and MARCO. Notably, KCR pretreatment attenuated CSF2-induced JAK2/STAT5 phosphorylation, ROS production, and phagocytosis, consistent with competitive interference with endogenous CSF2-CSF2R signaling. Together, these findings reveal KCR as a previously unrecognized T. gondii factor that targets the CSF2/CSF2R axis to recalibrate macrophage effector functions, expanding the repertoire of parasite strategies for cytokine pathway modulation and highlighting CSF2-CSF2R signaling as a potential interface for mechanistic and therapeutic investigation in toxoplasmosis.

Keywords:  CSF2; JAK2/STAT5 signaling; KCR; Toxoplasma gondii; immune evasion

DOI:  https://doi.org/10.1155/tbed/8426765
Nat Commun. 2026 May 13. pii: 4329. [Epub ahead of print]17(1):

Hierarchical small molecule inhibition of MYST acetyltransferases.

Xuemin Chen, Alexandra Castroverde, Minervo Perez, Ronald Holewinski, Kiall F Suazo, Rashmi Karki, Thorkell Andresson, Benjamin A Garcia, Jordan L Meier.

MYST lysine acetyltransferases (KATs) are a class of epigenetic enzymes critical for cellular function that constitute an emerging therapeutic target in cancer. Recently, several drug-like MYST inhibitors have been reported that show promise in preclinical models as well as in clinical trials of breast cancer. Understanding the specificity of these molecules is critical for their effective use as chemical probes. Here we apply an integrated profiling strategy to systematically define the potency and selectivity of drug-like MYST KAT inhibitors. First, we use optimized chemoproteomic profiling and histone acetylation biormarkers to study the industry-developed KAT inhibitor PF-9363. This reveals dose-dependent engagement of native KAT complexes, with hierarchical inhibition following the order KAT6A/B > KAT7 » KAT8 > KAT5. This pattern of target engagement is shared by the clinical candidate PF-8144. Next, we demonstrate how PF-9363's ability to disrupt capture of MYST complex members in chemoproteomic experiments can be leveraged to identify uncharacterized candidate members of these complexes, including the transcription factor FOXK2. Applying insights from these studies to WM-8014, WM-1119 and WM-3835, which have been extensively applied in the literature as MYST probes, highlights unexpected cross-inhibition and suggests a framework for how these small molecules and biomarkers may be applied to differentiate KAT6A/B and KAT7-dependent phenotypes. Finally, we benchmark the activity of PF-9363 in the NCI-60 cell line screen, providing evidence that its ability to engage KAT8 at elevated concentrations can drive acute growth inhibition. Collectively, our studies indicate the potential for MYST KAT inhibitors, including clinical candidates, to exhibit dose-dependent target engagement reminiscent of kinase inhibitors. The assays and biomarkers described here should find broad utility in assessing selective target engagement by this inhibitor class.

DOI: https://doi.org/10.1038/s41467-026-70574-1
mBio. 2026 May 13. e0037226

Composition and role of the vacuolar transporter chaperone complex in polyphosphate synthesis and infectivity in Trypanosoma cruzi.

Mayara S Bertolini, Miguel A Chiurillo, Roberto Docampo.

  Inorganic polyphosphate (polyP) is a linear polymer composed of three to several hundred orthophosphate units linked by high-energy phosphoanhydride bonds and is found in both prokaryotes and eukaryotes. In Trypanosoma cruzi, the causative agent of Chagas disease, polyP plays important roles in osmoregulation and persistence within host tissues and is synthesized by a polyP polymerase known as the vacuolar transporter chaperone (VTC) complex. This complex, localized to acidocalcisomes, is composed of Vtc1 and the catalytic subunit Vtc4. Using CRISPR/Cas9-mediated genome editing, we generated Vtc1 knockout (Vtc1-KO), Vtc4 single knockout (Vtc4-SKO), and conditional knockout lines for both subunits (Vtc1-CKO and Vtc4-CKO). Analysis of these mutants revealed essential roles for Vtc1 and Vtc4 in parasite proliferation, differentiation, and egress from mammalian host cells. Moreover, co-immunoprecipitation and proteomic analyses identified a novel component of the complex, termed TcVtc6, which associates with Vtc1 and Vtc4, forms part of the VTC complex, and is involved in polyP synthesis in Trypanosoma cruzi.
IMPORTANCE: Chagas disease affects millions of people across the Americas and remains a major unmet medical challenge. Here, we investigate the essentiality and molecular composition of the vacuolar transporter chaperone (VTC) complex in Trypanosoma cruzi, the causative agent of the disease. We identify a previously unrecognized component of this complex, which we term TcVtc6, and show that it is involved in polyphosphate synthesis. Functional analyses reveal that the VTC complex is indispensable for parasite differentiation and host cell egress, two processes critical for infectivity. Although the VTC complex is conserved in trypanosomatids, apicomplexans, fungi, and algae, it is absent from mammalian cells. This evolutionary divergence, together with the essential role of the pathway in infectious stages of T. cruzi, highlights the VTC complex as a promising and selective therapeutic target for the treatment of Chagas disease.

Keywords:  Trypanosoma cruzi; inorganic polyphosphate; inositol pyrophosphate; vacuolar transporter chaperone

DOI:  https://doi.org/10.1128/mbio.00372-26
Vet Pathol. 2026 May 11. 3009858261449082

Neutrophilic cholangitis associated with intracholangiocytic Hammondia protozoa confirmed in 2 dogs and suspected in 2 dogs.

Eunju April Choi, Devinn M Sinnott, Amira A Ahmed, Anibal G Armien, Karen Shapiro, Manigandan L Virapin.

  Four dogs with neutrophilic cholangitis were identified with intracholangiocytic apicomplexan protozoa. Two cases were biopsies, and both cases had gallbladder involvement. The other two cases were unexpected findings on autopsy. Immunohistochemistry against Toxoplasma gondii on all cases labeled the zoites. Internal transcribed spacer-1 polymerase chain reaction (PCR) performed on formalin-fixed paraffin-embedded samples was successful in the 2 biopsy cases, and subsequent sequencing identified >99% sequence identity to Hammondia sp. Of the biopsied dogs, 1 dog recovered successfully after antiprotozoal treatment while the other dog was euthanized due to poor response. The 2 autopsy cases were given immunosuppressive medication. Hammondia are within the Sarcocystidae family of apicomplexan parasites and are closely related to Neospora caninum. This study and the current literature support that Hammondia, specifically Hammondia heydorni, an organism that was previously considered nonpathogenic or minimally pathogenic, can rarely exhibit tropism to the biliary system and cause neutrophilic cholangitis, cholangiohepatitis, and cholecystitis in dogs.

Keywords:  Hammondia; canine; cholangitis; cholecystitis; gallbladder; liver; sarcocystidae

DOI:  https://doi.org/10.1177/03009858261449082
Microb Pathog. 2026 May 10. pii: S0882-4010(26)00275-5. [Epub ahead of print] 108549

Serial passage is associated with virulence attenuation in Neospora caninum and transcriptomic remodeling of invasion- and chronic-stage-associated pathways.

Kun Guo, Shui Yu, Na Yang, Xianmei Wang, Qun Liu, Yong Fu, Jing Liu.

  Neospora caninum is an obligate intracellular apicomplexan parasite and a major cause of abortion in cattle worldwide. However, the molecular basis underlying virulence attenuation during long-term in vitro passage remains poorly understood. Here, we performed comparative transcriptomic profiling between the virulent Nc1-09 strain and its attenuated derivative Nc1 to investigate transcriptional changes associated with virulence reduction. A total of 487 differentially expressed genes (DEGs) were identified. Functional enrichment analyses revealed prominent changes in pathways related to protein modification, host-parasite interaction, motility, and metabolism. Notably, multiple members of the surface antigen glycoprotein (SRS) family displayed marked transcriptional shifts, consistent with altered host cell interaction and immune-related functions. CRISPR/Cas9-mediated disruption of three representative DEGs (NCLIV_016320, NCLIV_024950, and NCLIV_022830) did not reproduce the attenuated phenotype, suggesting that disruption of these individual genes is insufficient to account for the full attenuated phenotype under the conditions tested. Gene set enrichment analysis further demonstrated systematic downregulation of protein modification-associated pathways in the attenuated strain. Overall, the data indicate that virulence attenuation in N. caninum is associated with coordinated transcriptional remodeling across multiple functional pathways rather than discrete gene loss.

Keywords:  Neospora caninum; SRS family; alternative splicing; host–parasite interaction; transcriptome; virulence attenuation

DOI:  https://doi.org/10.1016/j.micpath.2026.108549
Sci Rep. 2026 May 11.

Insights into SIRT2 inhibition from machine learning-assisted multi-level screening of the NCI database.

Laila Abdulmohsen Jaragh-Alhadad, Alaa H M Abdelrahman, Peter A Sidhom, Moustafa S Moustafa, Mahmoud A A Ibrahim.

  The nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase Sirtuin 2 (SIRT2) plays a regulatory function in diverse cellular processes and has been linked to aging and the development of neurodegenerative and cancerous diseases. Consequently, targeting SIRT2 has emerged as a promising anticancer therapeutic strategy; however, currently available SIRT2 inhibitors and modulators often exhibit limited potency and suboptimal selectivity. Herein, the NCI database, containing more than 230,000 compounds, was systematically screened using an optimized AttentiveFP model to identify small molecules with potential SIRT2-inhibitory activity. The trained model predicted 23,238 NCI compounds as potentially active, which were subsequently subjected to docking computations against SIRT2. Upon docking estimations, the top-ranked NCI compounds bound to SIRT2 were advanced for molecular dynamics simulations (MDS) throughout 300 ns, along with binding energy (ΔGbinding) computations utilizing the MM-GBSA approach. Among these, NCI243049, NCI407129, and NCI248613 unveiled superior binding affinities toward SIRT2 over 300 ns MDS compared to the reference inhibitor SirReal2, with ΔGbinding values of -74.3, -73.1, -71.5, and -47.8 kcal/mol, respectively. Post-MD analyses consistently supported the promising stability and binding profiles of the identified NCI compounds bound to SIRT2 throughout 300 ns MDS. The physicochemical and ADMET features of the identified NCI compounds were predicted, indicating their favorable oral bioavailability and pharmacokinetic profiles. Eventually, DFT computations were executed to assess the chemical reactivity of the identified NCI compounds. Collectively, these findings highlighted NCI243049, NCI407129, and NCI248613 as promising SIRT2 inhibitors, meriting further validation through experimental assays for cancer therapy.

Keywords:  DFT computations; ML-based virtual screening; Molecular dynamics simulations; NCI database; SIRT2

DOI:  https://doi.org/10.1038/s41598-026-52371-4
Elife. 2026 May 14. pii: RP104123. [Epub ahead of print]14

Identification of the regulatory elements and protein substrates of lysine acetoacetylation.

Qianyun Fu, Terry Nguyen, Bhoj Kumar, Parastoo Azadi, Y George Zheng.

  Short-chain fatty acylations establish connections between cell metabolism and regulatory pathways. Lysine acetoacetylation (Kacac) was recently identified as a new histone mark. However, regulatory elements, substrate proteins, and epigenetic functions of Kacac are not yet fully understood, hindering further in-depth understanding of acetoacetate-modulated (patho)physiological processes. Here, we created a chemo-immunological approach for reliable detection of Kacac, and demonstrated that acetoacetate serves as the primary precursor for histone Kacac. We report the enzymatic addition of the Kacac mark by the acyltransferases GCN5, p300, and PCAF, and its removal by the deacetylase HDAC3. Furthermore, we establish acetoacetyl-CoA synthetase as a key regulator of cellular Kacac levels. A comprehensive proteomic analysis has identified 139 Kacac sites on 85 human proteins. Bioinformatics analysis of Kacac substrates and RNA sequencing data reveal the broad impacts of Kacac on multifaceted cellular processes. These findings unveil pivotal regulatory mechanisms for the acetoacetate-mediated Kacac pathway, opening a new avenue for further investigation into ketone body functions in various pathophysiological states.

Keywords:  chromosomes; epigenetics; gene expression; histones; human; ketone body; lysine acetyltransferase; metabolism; protein post-translational modification

DOI:  https://doi.org/10.7554/eLife.104123
J Membr Biol. 2026 May 09. pii: 12. [Epub ahead of print]259(1):

Deciphering Membrane Pore Formation Mechanisms of Plasmodium falciparum Perforin-Like Protein 1 (PfPLP1).

Sanket B Patil, Subrata Dasgupta, Prasenjit Bhaumik.

  Membrane Attack Complex/Perforin (MACPF) domain proteins are β-pore forming toxins (β-PFTs) involved in the pathogenesis of various organisms. Among them, Perforin-like proteins (PLPs), produced by Plasmodium species, play essential roles in parasite invasion and egress. Due to increasing drug resistance in Plasmodium, PLPs represent promising but underexplored therapeutic targets, largely due to the lack of structural and mechanistic data. This study investigates the binding and pore formation mechanism of the Plasmodium falciparum PLP1 (PfPLP1), which is expressed during the human life cycle of the parasite. We modeled PfPLP1 structure and performed both all-atom and coarse-grained molecular dynamics simulations in soluble and membrane-associated states. PfPLP1 comprises two domains, a canonical MACPF domain and a β-pleated sheet domain- apicomplexan perforin β-domain (APCβ). Initial membrane binding is mediated by cationic residues at the base of the APCβ domain, which interact with the polar headgroups of the lipids from the host cell membrane. We analyzed the membrane-inserted tetrameric form where water molecules were observed to penetrate between the tetramer and the lipid bilayer, initiating pore opening. During this process, lipids reorganize into a toroidal edge to shield their hydrophobic tails, while water mixes with lipid headgroups in a disordered, heterogeneous fashion. Larger oligomeric assemblies show lateral displacement of lipids and a clear tendency to form pore-like structures. This study provides molecular insights into PfPLP1's membrane binding and pore-forming behavior in both monomeric and oligomeric forms. The outcome of this study would be applicable in understanding pore formation mechanism in other PLPs and similar toxins.

Keywords:   Plasmodium falciparum Perforin-Like Protein 1 (PfPLP1); MACPF domain proteins; MD-simulation; Membrane-interaction; Pore formation, Pore forming toxins

DOI:  https://doi.org/10.1007/s00232-026-00376-5
Mol Biol Rep. 2026 May 11. pii: 741. [Epub ahead of print]53(1):

Molecular mechanisms of SIRT1 in regulating ageing and related intervention strategies.

Yuting Sun, Xueling Dai, Yajun Lin, Yaxuan Sun.

  Silent mating type information regulation 1 (SIRT1), a core molecule bridging energy metabolism and ageing modulation, relies on its nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase activity and pathway crosstalk to form a key regulatory network governing ageing. This review focuses on the central regulatory role of SIRT1 in cellular senescence, integrating its multidimensional mechanisms in deoxyribonucleic acid (DNA) damage response, inflammatory microenvironment modulation, autophagic function remodeling, and maintenance of energy metabolic homeostasis. Meanwhile, we summarized the intervention strategies targeting SIRT1 (e.g., small-molecule compounds and natural extracts) and the differences in their action targets, clarifying their translational potential in the prevention and treatment of ageing-related diseases. We further highlight emerging evidence on sex-specific differences, model specificity, and evolutionary conservation that shape SIRT1's role in ageing. This review aims to provide a systematic perspective for in-depth understanding of the SIRT1-mediated ageing regulatory network, and offer a reference for basic anti-ageing research, optimization of precise intervention strategies, and screening of therapeutic targets for related diseases.

Keywords:  Apoptosis; Autophagy; Cellular senescence; Energy metabolism; SIRT1

DOI:  https://doi.org/10.1007/s11033-026-11913-9
Biol Chem. 2026 May 26. 407(1-3): 25-66

Mechanistic insights on spatiotemporal control of Ras-signaling.

Clotilde Charrier, Sascha Mrachacz, Sabrina Schulze, Michael Lammers.

  Proteins of the Ras-family are guanine nucleotide binding proteins (GNBPs) involved in a variety of fundamental cellular processes, including cell proliferation, cell differentiation, cytoskeleton dynamics, vesicular processes and intracellular transport. A dysregulation of Ras-signaling has been found to be causative for the development of diseases, such as diverse cancer types, RASopathies, neurodegenerative diseases and ciliopathies. Ras-proteins cycle between a GTP-bound on-state and a GDP-bound off-state. Ras-proteins show low intrinsic rates for nucleotide exchange and nucleotide hydrolysis. They need guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) to accelerate both functions in order to act as true molecular switches in the physiological context. Ras-proteins and their regulators/effectors are targets of post-translational modifications (PTMs) such as phosphorylation, ac(et)ylation, lipidation and ubiquitination. These PTMs regulate their activity, subcellular localization and turnover. In a biological perspective, PTMs are essential components for cellular signaling cascades and for molecular pattern formation. Bacterial pathogens use PTMs of Ras-proteins to allow efficient infection processes. Besides, modifications of Ras-proteins were shown to be of therapeutic potential in oncogenic variants such as Ras G12C. In this review, we summarize current knowledge on Ras-signaling, while emphasizing PTMs as dynamic signaling hubs for its precise spatiotemporal control.

Keywords:  Ras; acetylation; guanine nucleotide binding proteins; post-translational modification

DOI:  https://doi.org/10.1515/hsz-2025-0243
Trends Biochem Sci. 2026 May 14. pii: S0968-0004(26)00109-X. [Epub ahead of print]

Post-translational modifications as key regulators of proline metabolism.

Nina Durand, Arnould Savouré, Sandrine Lebreton.

  Post-translational modifications (PTMs) are emerging as crucial regulators of proline metabolism, a pathway central to redox homeostasis, stress adaptation, and disease progression conserved across species. Beyond transcriptional regulation, PTMs such as phosphorylation, acetylation, and ubiquitination fine-tune the activity, stability, and localization of proline metabolic enzymes, including those involved in its biosynthesis and catabolism. Advances in proteomics and structural biology now provide insights into how these reversible modifications modulate enzyme oligomerization and metabolic flux, with involvement in plant stress tolerance and cancer cell survival. Here, we synthesize recent observations across kingdoms, discuss how PTMs integrate into metabolic control, and highlight future directions for exploiting PTM-based regulation in agriculture and human health.

Keywords:  cancer metabolism; evolutionary conservation; post-translational modifications; proline metabolism; redox regulation; stress adaptation

DOI:  https://doi.org/10.1016/j.tibs.2026.04.009
bioRxiv. 2026 Feb 23. pii: 2026.02.22.707301. [Epub ahead of print]

HDAC11 Regulates RNA Splicing via De-Fatty Acylation of SF3B2.

Jenna Clements, Sung Jung, Ji Cao, Lei Sun, Ana Carolina Ghezzi, Mitchell Gaylen, La'Quan Reid, Changmin Peng.

Histone deacetylase 11 (HDAC11) is a lysine de-fatty acylase whose cellular substrates and mechanisms remain incompletely defined. Here, using metabolic labeling, mass spectrometry, click chemistry, and standard molecular biology, we show that SF3B2 is modified by lysine myristoylation at K10 and that HDAC11 efficiently removes this modification in cells, establishing SF3B2 as a direct enzymatic substrate. A de-myristoylation mimetic mutant (SF3B2 K10R) exhibits altered pre-mRNA binding activity in a context-dependent manner. In HCC cells, loss of SF3B2 lysine myristoylation enhances SF3B2 association with androgen receptor (AR) splice variant loci and promotes alternative splicing towards the AR-v7 variant. Consistently, HDAC11 overexpression increases, and HDAC11 knockdown decreases, the AR-v7/AR-FL splice isoform ratio in HCC cells in a manner requiring HDAC11 catalytic activity and recapitulated by SF3B2 K10R. In contrast, modulation of HDAC11 does not alter AR splicing in prostate cancer cells, indicating cell type specific regulation. Together, these findings establish lysine myristoylation as a reversible regulatory modification on a spliceosomal component and reveal HDAC11-catalyzed de-myristoylation of SF3B2 as a mechanism that can tune alternative splicing in liver cancer cells.
In Brief: Clements et al. utilize metabolic labelling, mass spectrometry, click chemistry, and protein and RNA biochemistry to establish that a histone deacetylase enzyme, HDAC11, can influence RNA splicing through de-fatty acylation of the RNA splicing factor SF3B2. De-fatty acylation of SF3B2 at K10 by HDAC11 modulates SF3B2's pre-mRNA binding to AR splice variant loci, thereby driving alternative splicing of the AR-v7 variant in a cell type dependent manner. This work provides direct mechanistic evidence linking an HDAC to RNA splicing, identifies a reversible lipid modification on SF3B2, and expands current understanding of post-translational regulation of spliceosomal proteins and HDAC11 de-fatty acylation substrates.
Highlights: HDAC11 de-fatty-acylates SF3B2 at K10, revealing a previously unrecognized modification on SF3B2.SF3B2 de-fatty acylation enhances alternative splice-site binding in liver cancer cells.HDAC11 regulates RNA splicing through enzymatic de-fatty acylation of a spliceosomal protein.

DOI: https://doi.org/10.64898/2026.02.22.707301
PLoS Pathog. 2026 May 11. 22(5): e1014214

Spatiotemporal dynamics of signal dependent exocytosis and parasitophorous vacuolar membrane rupture during Plasmodium falciparum egress.

Watcharatip Dedkhad, Tia Tran, Manuel A Fierro, Carrie Brooks, Vasant Muralidharan.

Malaria, caused by intracellular Plasmodium falciparum parasites, remains a major global health concern. These parasites reside and replicate within a vacuole in host red blood cells. Egress of daughter parasites out of the vacuolar and host membranes is tightly regulated via a complex mechanism. Prior studies have suggested that a cyclic-GMP driven calcium signaling pathway leads to the signal-dependent exocytosis of egress-specific vesicles that discharge several proteases into the parasitophorous vacuole. However, signal-dependent exocytosis during egress has not yet been observed in live parasitized RBCs. We targeted the exocytosis reporter, superecliptic pHlourin or SEP, to these egress-specific vesicles and utilized live imaging to observe exocytosis. The spatiotemporal relationship between exocytosis and the breakdown of the parasitophorous vacuolar membrane (PVM) as well as parasite egress was also determined using a fluorescent reporter fused to EXP2. Our data showed that exocytosis is triggered as early as 3 hours prior to merozoite egress. These data suggest that the PVM rupture occurs at a single site and rapidly expands from that initial site of rupture, releasing the merozoites into the RBC. This is followed by RBC membrane rupture and egress of merozoites. Using conditional mutants of Plasmodium endoplasmic reticulum calcium-binding protein (PfERC), we demonstrate that loss of PfERC inhibits signal-dependent exocytosis of egress-specific vesicles. Together, these data demonstrate that signal-dependent exocytosis of egress-specific vesicles starts well before merozoites are formed via cytokinesis, PVM ruptures at a single site, and that PfERC is required for exocytosis of egress-specific vesicles.

DOI: https://doi.org/10.1371/journal.ppat.1014214
New Phytol. 2026 May 14.

Cross-kingdom communication between plants and parasitic nematodes.

Christopher A Bell, Lida Derevnina, Sebastian Eves-van den Akker.

  Plant-parasitic nematodes and their hosts engage in a continuous exchange of signals cross-kingdom. On the one hand, parasites exploit host-derived metabolites, proteins, and RNAs to sense host identity, proximity, and condition - and as a basis for manipulating host processes to their benefit. On the other hand, hosts respond to nematode-derived pheromones, proteins, and metabolites to either subvert or accommodate parasitism. Our recent understanding is that microbes play a role mediating, at least in part, a communication, which ultimately shapes the developmental trajectories of both host and parasite, in concert. In this Tansley insight, we review the current understanding of communication between plants and parasitic nematodes, framed by the developmental timeline. We focus on notable, reciprocal signals between plant and parasite that gate key life cycle transitions in the parasite, while acknowledging that these processes are embedded within, and inseparable from, a plethora of other signals - and indeed communication with other organisms. The frequency, reciprocity, and gravity of the exchange leads us to argue that it is best described as a nuanced communication, in which parasitism succeeds or fails based on interpretation and response.

Keywords:  biotrophic interaction; cross‐kingdom communication; hatching; host approach; host arrival; plant‐parasitic nematodes

DOI:  https://doi.org/10.1111/nph.71283
Autophagy. 2026 May 10.

Acetylated Vps1 initiates autophagy and regulates the sorting nexin dynamics essential for pathogenicity in fusarium graminearum.

Xin Chen, Xiaomin Chen, Zhenyu Fang, Yunfei Long, Yan Cai, Yakubu Saddeeq Abubakar, Naweed I Naqvi, Zonghua Wang, Wenhui Zheng.

  Macroautophagy/autophagy is a dynamic recycling process that maintains cellular homeostasis and is closely linked to fungal development and pathogenicity. However, the mechanisms underlying the maintenance of autophagy homeostasis remain largely unclear in phytopathogenic fungi. In this study, we identified the FgHat2-FgVps1-FgSnx4 module as a key regulator of autophagy homeostasis in Fusarium graminearum. We show that the initiation of autophagy requires acetylation of the dynamin-like GTPase FgVps1 at lysine 216 by the histone acetyltransferase FgHat2. This modification promotes the interaction between FgVps1 and the autophagy protein FgAtg8 and facilitates the endosomal release of the sorting nexin FgSnx4. Released FgSnx4 is essential for directing FgAtg9 trafficking to the phagophore and for interacting with FgAtg8 through its N-terminal Atg8-family interacting motif (AIM), thereby ensuring proper modulation of FgAtg8 during autophagy. Together, these findings reveal an acetylation-dependent mechanism that coordinates autophagy, providing new insights into the regulation of autophagy in phytopathogenic fungi.

Keywords:  Acetylation; Dynamin-like GTPase; autophagy; fusarium graminearum; sorting nexin

DOI:  https://doi.org/10.1080/15548627.2026.2672701