bims-toxgon 2025-10-26 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–10–26
eighteen papers selected by
Lakesh Kumar, BITS Pilani

A nucleoside transporter on the mitochondria of T. gondii is essential for maintaining normal growth of the parasite.
Targeted inhibition of human Tankyrase-1 (TNKS1) by ZT-5483 exhibited Anti-Parasitic activity in Toxoplasma gondii: An in silico-based, high-throughput virtual screen and in vitro approach.
Purification and Characterization of Immunoglobulin Y (IgY) Targeting Surface Antigen 1 (SAG1) of Toxoplasma gondii.
TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control.
Enhancing pre-sexual and sexual differentiation of Toxoplasma gondii using retinal epithelial cells and intestinal organoids.
Molecular detection of Toxoplasma gondii in wild oysters and seawater on the southeast coast of South Korea.
Endogenous structure of antimalarial target PfATP4 reveals an apicomplexan-specific P-type ATPase modulator.
Plasmodium berghei IMC1j interacts with δ-tubulin to orchestrate subpellicular microtubule organization in ookinetes.
GCN5L: a critical target in energy metabolism pathways.
Characterization of a phosphoinositide-binding protein containing a PHOX homology domain in the malaria parasite Plasmodium falciparum.
Trivalent chromium interacts directly with acetylated lysine.
Histone Deacetylase 6 Inhibits STING-Dependent Antiviral Immunity via Site-Specific Deacetylation.
Cryptosporidium oocyst wall proteins are true components of the oocyst wall and COWP8 is not required for parasite transmission.
Deacetylation of TALDO1 by HDAC6 promotes glycolysis and nasopharyngeal carcinoma progression through a moonlighting function.
Global comparative structural analysis of responses to protein phosphorylation.
Avian malaria and the overlooked metabolic pathways underlying mosquito-Plasmodium interactions.
SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.
Different patterns of Toxoplasma gondii infection epidemiology in the general population, animal contact workers, and blood donors in southeastern China between 2019 and 2023: a cross-sectional study.

Parasit Vectors. 2025 Oct 21. 18(1): 418

A nucleoside transporter on the mitochondria of T. gondii is essential for maintaining normal growth of the parasite.

Jiahui Qian, Liyu Guo, Yilian Yang, Zhengming He, Mingfeng He, Chengjie Chen, Yifan Luo, Jiayin Xu, Senyang Li, Rui Fang.

   BACKGROUND: Toxoplasma gondii invades almost all nucleated cells of warm-blooded animals, but T. gondii lacks the ability to synthesize purines; therefore, it must scavenge purines from host cells to fuel its proliferation and propagation. Through exogenous expression, the adenosine transporter TgAT1 has been validated for its ability to transport both oxypurine nucleosides and nucleobases across the parasite plasma membrane, although its affinity for the substrate is low. Further studies have shown that T. gondii also has a high-affinity purine and pyrimidine nucleoside transport system (TgAT2), but this protein has not been identified thus far.
METHODS: Here, we identified three novel nucleoside transporters in T. gondii by homology alignment. Using immunofluorescence staining, we found that TgNT1, TgNT2, and TgNT3 are localized to the mitochondria, plasma membrane, and endoplasmic reticulum (ER), respectively. We also performed conditional knockout of TgNT1 and direct knockout of TgNT2/TgNT3 using CRISPR/Cas9 technology.
RESULTS: TgNT1 is crucial for the in vitro growth and proliferation of T. gondii, whereas the other two genes are dispensable. Conditional depletion of TgNT1 impairs multiple metabolic pathways in both the mitochondria and cells of the parasite, with the most significant changes manifesting in the levels of various nucleosides. Carbon metabolism is also affected, as evidenced by alterations in metabolite levels within both the electron transport chain and the tricarboxylic acid cycle. The impairment of adhesion and invasion functions appears to be strongly associated with a reduction in the content of the initial lipid involved in glycosylphosphatidylinositol (GPI)-anchored lipid modification, which may underlie the inhibition of T. gondii's invasive capacity. Notably, TgNT1 is the first nucleoside transporter protein that is localized in the mitochondria of T. gondii. Given that TgNT1 has no homologous proteins in mammals, it holds promise as a potential drug target.
CONCLUSIONS: TgNT1, a nucleoside transporter located in the mitochondria of T. gondii, is essential for maintaining the normal growth of the parasite.

Keywords:   T. gondii ; Mitochondrial; Nucleoside transporter

DOI:  https://doi.org/10.1186/s13071-025-07054-w
Mol Biochem Parasitol. 2025 Oct 16. pii: S0166-6851(25)00041-6. [Epub ahead of print] 111705

Targeted inhibition of human Tankyrase-1 (TNKS1) by ZT-5483 exhibited Anti-Parasitic activity in Toxoplasma gondii: An in silico-based, high-throughput virtual screen and in vitro approach.

Yasser Alraey.

   BACKGROUND AND AIM: Toxoplasmosis is considered one of the leading causes of mortality resulting from foodborne illness. This disease is caused by infection with the Toxoplasma gondii parasite. Given the serious side effects and recurrence of resistance, there is an unmet need to develop effective novel drugs with low toxicity against T. gondii. This study aims to identify novel anti-parasitic compounds targeting human Tankyrase-1 involved in T. gondii infection using bioinformatics and in vitro approaches.
METHODS: For lead identification, high-throughput virtual screening (HTVS) against the ChemBridge library was followed by Protein-Ligand Interaction Profiler, GROMACS, and GMX_MMPBSA techniques. Human TNKS1 (PARP5A) colorimetric assay was performed. The RH-2F strain of T. gondii tachyzoites that expressed beta-galactosidase was maintained in the human foreskin fibroblasts (HFFs) to determine the parasite growth-inhibitory efficacy of the lead candidate. MTT assay was used to detect the inhibition rate on host cell viability.
RESULTS: HTVS identified ZT-5483 with favorable binding affinities of 8.8kcal/mol towards TNKS1. Molecular dynamic simulations demonstrated stable binding interactions for ZT-5483 and TNKS1 with Root Mean Square Deviation values around 0.04nm. The ΔG binding calculation was -43.09kcal/mol, favoring sturdy binding. ADME analysis supported favorable small-molecule characteristics. ZT-5483 dose responsively inhibited TNKS1 activity with an IC50 value of 140.8nM. ZT-5483 suppressed the parasite growth with an IC50 value of 297.8nM. The compound's cytotoxicity to HFF host cells (TD50 value) was determined to be 3354nM. The in vitro toxicity index (TI) of ZT-5483 was 11.26 based on the IC50 and TD50 values.
CONCLUSION: Together, these ﬁndings suggest that ZT-5483 could be a potential novel candidate against T. gondii. However, further preclinical and pharmacological evaluations are warranted.

Keywords:  TNKS1; Toxoplasma gondii; Toxoplasmosis; WNT/β-catenin; parasite infection

DOI:  https://doi.org/10.1016/j.molbiopara.2025.111705
Antibodies (Basel). 2025 Sep 26. pii: 81. [Epub ahead of print]14(4):

Purification and Characterization of Immunoglobulin Y (IgY) Targeting Surface Antigen 1 (SAG1) of Toxoplasma gondii.

Enrique Adrián Herrera-Aguirre, Diana León-Núñez, Jaime Marcial-Quino, Saúl Gómez-Manzo, César Augusto Reyes-López, Yolanda Medina-Flores, Olga Mata-Ruíz, Lizbeth Xicotencatl-García, Hector Luna-Pastén, Luz Belinda Ortiz-Alegría, Nury Pérez-Hernández, Magdalena Escorcia, Dolores Correa, Fernando Gómez-Chávez.

  Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite responsible for toxoplasmosis, a disease with significant health implications for humans and animals. The surface antigen 1 (SAG1) of T. gondii is a major immunodominant protein that facilitates host cell invasion, making it an ideal target for diagnostic and therapeutic interventions. Immunoglobulin Y (IgY), the primary antibody in avian species, offers unique advantages over mammalian IgG, including easier animal care, lower costs, high-yield production, and potential passive immunization.
OBJECTIVES: This study aimed to induce, purify, and characterize IgY antibodies targeting T. gondii SAG1 from hen egg yolks.
METHODS: The coding region of the mature portion of T. gondii SAG1 was amplified by PCR, cloned into the pET32a(+) vector for heterologous expression in E. coli. The recombinant SAG1 (rSAG1) was purified by affinity chromatography and used to immunize hens. IgY was extracted from egg yolks using PEG. SDS-PAGE and spectrophotometry were used to evaluate purity and concentration. By ELISA, Western blot, and flow cytometry, the specificity of IgY was assessed against recombinant and endogenous, native, and denatured SAG1.
RESULTS: Purified IgY demonstrated strong recognition of both recombinant and native SAG1 in ELISA and Western blot, and against T. gondii tachyzoites by flow cytometry.
CONCLUSIONS: SAG1-specific IgY was produced in a pure form; it could be helpful in research, diagnosis, and treatment at low costs on a larger production scale, with minimal animal harm.

Keywords:  IgY; SAG1; Toxoplasma gondii; antibodies

DOI:  https://doi.org/10.3390/antib14040081
BMC Biol. 2025 Oct 21. 23(1): 316

TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control.

Serena Ghisletti, Marta Russo.

  Mitochondrial enzymes are increasingly recognized for their ability to translocate to the nucleus, where they generate metabolites essential for epigenetic regulation and gene expression. Yet, whether this phenomenon broadly involves metabolic enzymes or is restricted to specific subunits remains unclear. In this review, we assess current evidence, highlight knowledge gaps, and suggest future directions on the nuclear localization and functions of metabolic enzymes, with a focus on acyl-CoA producers. Emerging studies reveal multiple mechanisms guiding these enzymes to chromatin for localized metabolite synthesis. Key questions concern nuclear import machinery, chromatin interactions, and the regulatory impact of their activity.

Keywords:  Histone modifications; Metabolism; Mitochondrial enzymes; Transcriptional regulation

DOI:  https://doi.org/10.1186/s12915-025-02423-4
Cell Rep. 2025 Oct 16. pii: S2211-1247(25)01222-7. [Epub ahead of print]44(10): 116451

Enhancing pre-sexual and sexual differentiation of Toxoplasma gondii using retinal epithelial cells and intestinal organoids.

Saira Cancela, Florencia Sena, Romina Pagotto, Martina Crispo, Maria E Francia, Mariela Bollati-Fogolín.

  Toxoplasmosis, caused by Toxoplasma gondii, is a major global health concern due to its high prevalence, zoonotic transmission, and economic impact on livestock. The parasite's life cycle includes asexual, pre-sexual, and sexual stages, the latter responsible for oocyst shedding and genetic recombination. Understanding sexual differentiation is critical, but access has been limited because these stages occur only in the feline intestinal epithelium. Recent studies identify host metabolic cues and the microrchidia (MORC) protein complex as regulators of sexual commitment. We optimize in vitro approaches to enrich pre-sexual and sexual stages by combining a human retinal epithelial cell line and murine intestinal organoids with FELIX medium, which mimics feline intestinal biochemistry, and conditional MORC depletion. This system increases stage-specific gene expression and marker detection, demonstrating synergistic effects of host environment and genetic regulation. Our findings provide accessible models to study T. gondii sexual differentiation, with implications for controlling transmission and genetic diversity.

Keywords:  CP: Microbiology; CP: Stem cell research; Toxoplasma gondii; feline intestinal environment; in vitro models; intestinal organoids; life cycle; sexual differentiation; stage conversion

DOI:  https://doi.org/10.1016/j.celrep.2025.116451
Food Microbiol. 2026 Mar;pii: S0740-0020(25)00205-9. [Epub ahead of print]134 104925

Molecular detection of Toxoplasma gondii in wild oysters and seawater on the southeast coast of South Korea.

Hyejoo Shin, Sooji Hong, Seungwan Ryoo, Jong-Yil Chai, Bong-Kwang Jung.

  Toxoplasma gondii is the most common parasitic protozoan infecting approximately two billion people worldwide. Among various sources of infection with T. gondii, marine ecosystems, including marine bivalves, have been identified as a significant reservoir for the parasite. This study aimed to assess the potential risk of T. gondii through seafood consumption in South Korea. We surveyed the T. gondii GRA7 gene in wild oysters, farmed oysters, and seawater collected from the southeast coastal areas, monthly from April to August 2021. The gene was sequenced using the Sanger sequencing method, and 98.4 %-100 % identity to the T. gondii GRA7 gene was confirmed. Based on sequencing results, the overall prevalence of T. gondii was 1.3 % (4/300) in wild oysters and 6.6 % (3/45) in seawater, while all farmed oysters were negative throughout the survey. These findings suggest a low role of bivalves in T. gondii contamination in marine environments, highlighting the need for further investigation in South Korea. In addition, it is crucial to enhance inspection protocols for various food products contaminated with T. gondii and increase public awareness.

Keywords:  Molecular detection; Oyster; Prevalence; Seawater; South Korea; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.fm.2025.104925
Nat Commun. 2025 Oct 20. 16(1): 9092

Endogenous structure of antimalarial target PfATP4 reveals an apicomplexan-specific P-type ATPase modulator.

Meseret T Haile, Anurag Shukla, James Zhen, Michael W Mather, Suyash Bhatnagar, Joanne M Morrisey, Zhening Zhang, Akhil B Vaidya, Chi-Min Ho.

The Plasmodium falciparum sodium efflux pump PfATP4 is a leading antimalarial target, but suffers from a lack of high-resolution structural information needed to identify functionally important features in conserved regions and guide rational design of next generation inhibitors. Here, we determine a 3.7 Å cryoEM structure of PfATP4 purified from CRISPR-engineered P. falciparum parasites, revealing a previously unknown, apicomplexan-specific binding partner, PfABP, which forms a conserved, likely modulatory interaction with PfATP4. The discovery of PfABP presents an unexplored avenue for designing PfATP4 inhibitors.

DOI: https://doi.org/10.1038/s41467-025-64815-y
mBio. 2025 Oct 21. e0266925

Plasmodium berghei IMC1j interacts with δ-tubulin to orchestrate subpellicular microtubule organization in ookinetes.

Gang He, Yonghui Feng, Dawei He, Yue Hu, Duo Wang, Sicong Wang, Xiaodan Sun, Shuangrui Shi, Tianyu Yang, Xueyuan Hu, Yaoguo Huang, Liwang Cui, Yaming Cao, Xiaotong Zhu.

  Apicomplexan parasites possess specialized structures for cell invasion and replication, notably the inner membrane complex (IMC) and the subpellicular microtubules (SPMTs) situated beneath it. SPMTs are thought to interact with proteins embedded in or associated with the IMC. The cytosolic side of the IMC contains a network of proteins known as alveolins. This study focuses on a specific alveolar protein, Plasmodium berghei IMC1j (PbIMC1j). We found that PbIMC1j undergoes palmitoylation and is predominantly expressed in ookinetes. Gene knockout analysis revealed that the absence of PbIMC1j leads to defects in parasite asexual stage fitness and virulence, alters ookinete morphology, and impairs motility and/or infectivity in both ookinetes and sporozoites. Deletion analyses indicated that the C-terminal region containing the coiled-coil (CC) domain is required for proper targeting to and function within the IMC. Immunoprecipitation analysis of PbIMC1j demonstrated the role of the IMCp domain in mediating interactions with and stabilizing the expression of the IMC protein ISC1 and the SPMTs component δ-tubulin (TubD). In ookinetes devoid of TubD, the SPMTs were disorganized, mirroring the defects observed during the zygote-to-ookinete transition in the PbIMC1j-deficient strains. Overall, our study highlights the importance of the PbIMC1j protein in parasite fitness, SPMT organization, and ookinete motility mediated through its IMCp and CC domains.IMPORTANCEMalaria parasites depend on an inner membrane complex (IMC) and subpellicular microtubules (SPMTs) to maintain their shape, motility, and ability to replicate. This study demonstrates that knocking out or disrupting the PbIMC1j protein adversely affects asexual stage fitness, virulence, and the morphology of ookinetes, while also decreasing the motility of ookinetes in P. berghei. Furthermore, PbIMC1j interacts and stabilizes the proteins ISC1 and δ-tubulin, underscoring its role in regulating the IMC and SPMTs.

Keywords:  alveolins; fitness; inner membrane complex; invasion; malaria; δ-tubulin

DOI:  https://doi.org/10.1128/mbio.02669-25
Front Cell Dev Biol. 2025 ;13 1671546

GCN5L: a critical target in energy metabolism pathways.

Yushun Kou, Ruiling Ma, Yiyuan Wang, Xiaojie Chen, Bin Li, Tao Wu, Yuanhui Gu, Lin Yi.

  GCN5L (GCN5-like protein), as a core component of a novel epigenetic-regulatory complex, exerts precise control over mitochondrial metabolic enzyme activity through acetylation modifications. It not only drives energy production but also regulates key processes like lipid metabolism and cellular stress responses. As research on GCN5L advances, exploring its specific regulatory mechanisms and functionality across physiological states has drawn growing interest from researchers. Drawing on 76 studies from CNKI, PubMed, and Web of Science, this review synthesizes current research advances on GCN5L. It aims to elucidate GCN5L's physiological significance as a critical target in energy metabolism, providing valuable references for related disciplines and advancing both theoretical understanding and practical applications in metabolic regulation.

Keywords:  GCN5L; cellular stress; clinical applications; energy metabolism; epigenetics

DOI:  https://doi.org/10.3389/fcell.2025.1671546
Sci Rep. 2025 Oct 22. 15(1): 36867

Characterization of a phosphoinositide-binding protein containing a PHOX homology domain in the malaria parasite Plasmodium falciparum.

Stéphanie Roucheray, Dominik Stastny, Harpreet Kaur, Dana Tahotna, Joel B Dacks, Peter Griac, Dave Richard.

  Phosphoinositides (PIPs), are key regulators of membrane identity and vesicular trafficking. By dynamically shaping the lipid composition of intracellular membranes, PIPs help ensure the specificity of cargo delivery. In apicomplexan parasites such as Plasmodium falciparum, the biogenesis of the specialized secretory organelles involved in erythrocyte invasion (named rhoptries, micronemes, and dense granules), remains poorly understood, particularly regarding how proteins are sorted and specifically targeted to their respective destinations. Our hypothesis is that PIPs might play a role in this process. We here present our characterization of the P. falciparum protein Pf3D7_0704400, a putative PIP-binding protein containing a PX domain. We named this protein PfPX2, following the previously characterized PX domain-containing protein PfPX1. In silico structural analysis revealed that the PfPX2 PX domain contains both canonical and non-canonical PIP-binding motifs and a positively charged binding pocket. Lipid binding assays showed that the PfPX2 PX domain can bind all species of PIPs with a preference for PI3P, PI5P and PI(3,5)P2. Immunofluorescence assays demonstrated that PfPX2 localized to the Golgi apparatus and the micronemes in developing schizonts. Moreover, proximity labelling enabled the identification of protein such as PfSortilin, the clathrin heavy chain and PfDyn1 as potential interactors of PfPX2. Globally, these data suggest that PfPX2 is a PIP-binding protein potentially implicated in vesicular trafficking between the Golgi apparatus and the micronemes. Our bioinformatics analyses identified PX2 orthologues across apicomplexans and indeed other alveolates, raising the possibility that this protein plays a role in a broad range of medically, agriculturally, and environmentally relevant organisms.

Keywords:  Golgi; Malaria; PX domain; Phosphoinositides; Protein trafficking

DOI:  https://doi.org/10.1038/s41598-025-20974-y
J Trace Elem Med Biol. 2025 Oct 18. pii: S0946-672X(25)00195-6. [Epub ahead of print]92 127782

Trivalent chromium interacts directly with acetylated lysine.

Rachel M Wise, Ting Jiang, Idoia Meaza, Changjian Feng, John Pierce Wise, Ke Jian Liu, Xixi Zhou.

   BACKGROUND: Hexavalent chromium Cr(VI), a well-established human carcinogen, induces systemic toxicity affecting reproductive, neurological, hepatic, and immune systems. The broad spectrum of its toxicity implies mechanisms of action that transcend organ-specific or cell type-restricted pathways. Protein interactions have been proposed as a mechanism underlying Cr(VI) toxicity and carcinogenicity.
OBJECTIVE AND METHODS: To address gaps in understanding the molecular effect of Cr(VI), particularly the distinct roles of its two stable oxidation states-Cr(VI) and the trivalent form Cr(III) -we employed high-resolution mass spectrometry to identify the protein targets, compare valence-state-specific interactions (Cr(VI) vs. Cr(III)), and map the specific amino acid residues involved.
RESULTS AND CONCLUSIONS: In synthesized histone peptides, we demonstrated that it is Cr(III), rather than Cr(VI), that directly binds to acetylated lysine residues. Further, in cellular models exposed to Cr(VI), we identified 15 Cr-binding proteins, all of which were acetylated, with site-specific information of interacting amino acids. Collectively, these findings provide new evidence that Cr(III), generated via intracellular reduction of Cr(VI), directly binds to post-translationally modified proteins on acetylated lysine residues. This work advances a molecular mechanism wherein Cr(VI) exerts toxicity via its reduced trivalent form, Cr(III), highlighting the critical putative role of protein acetylation in mediating Cr-induced damage.

Keywords:  Acetylation; Chromium; Mass Spectrometry

DOI:  https://doi.org/10.1016/j.jtemb.2025.127782
J Biol Chem. 2025 Oct 22. pii: S0021-9258(25)02693-6. [Epub ahead of print] 110841

Histone Deacetylase 6 Inhibits STING-Dependent Antiviral Immunity via Site-Specific Deacetylation.

Min Qu, Dali Wei, Qunhua Ke, Pengyuan Cheng, Yiyuan Ma, Berihun Afera, Ke Guo, Miaomiao Li, Xiangping Yin, Xiangwei Wang, Jianlin Han, Yuefeng Sun.

  Histone deacetylase HDAC6 is a critical regulator of antiviral innate immunity, but its precise molecular mechanisms during RNA viral infection remain incompletely understood. In this study, we demonstrate that HDAC6 depletion (via siRNA knockdown or pharmacological inhibition) significantly suppresses vesicular stomatitis virus (VSV) replication. Further analysis revealed that HDAC6 modulates innate immune signaling by targeting the stimulator of interferon genes (STING) pathway, thereby attenuating type I interferon (IFN) responses. Mechanistically, HDAC6 directly interacts with STING and catalyzes its deacetylation at lysine 338 (K338). This post-translational modification impedes TBK1 recruitment by altering STING acetylation status, ultimately impairing STING phosphorylation at serine 366 (S366). Functional validation showed that overexpression of a STING with K338Q acetylation-mimetic mutant confers cellular resistance to VSV infection, establishing HDAC6-mediated STING deacetylation as a pivotal regulatory checkpoint in the antiviral response.

Keywords:  Deacetylation; HDAC6; Innate immunity; Interferon; STING; VSV

DOI:  https://doi.org/10.1016/j.jbc.2025.110841
PLoS Pathog. 2025 Oct;21(10): e1013561

Cryptosporidium oocyst wall proteins are true components of the oocyst wall and COWP8 is not required for parasite transmission.

Ross Bacchetti, Sarah Stevens, Leandro Lemgruber, Mariana Azevedo Gonzalez Oliva, Emma M Sands, Konstantinos Alexandrou, Michele Tinti, Lee Robinson, Jack C Hanna, Simona Seizova, Peyton Goddard, Massimo Vassalli, Mattie Christine Pawlowic.

Cryptosporidiosis is a significant cause of diarrhoeal disease contributing to substantial morbidity and mortality for the immunocompromised and for young children, especially those who are malnourished. There are no vaccines and no effective treatments for these patients. Cryptosporidium parasites are transmitted as an oocyst, which is composed of a hardy oocyst wall that protects parasites in the environment. Oocysts are often waterborne, and are resistant to common water treatments, including chlorination. Little is understood about how the Cryptosporidium oocyst is constructed, its composition, and the how it resists chlorination. A family of nine Cryptosporidium Oocyst Wall Proteins (COWPs) is predicted from the genome. However, due to the technical challenges of working with this parasite in the laboratory, only cowp1 has been investigated to date. Using CRISPR/Cas9, fluorescent fusions were generated for the remaining members of the family, COWPs 2-9. Microscopy confirms that all COWPs localise to the oocyst wall. Further, COWPs 2-4 appear to localise specifically to the oocyst suture, the site from which parasites emerge from the oocyst during infection. Cowp 6 and 8 were observed to be expressed by female parasites. These proteins localise to puncta consistent with organelles called wall forming bodies. These organelles store and then secrete material to form the oocyst wall. Parasites lacking cowp8 produce viable oocysts that have typical oocyst morphology. Cowp8 knockout oocysts are transmissible under laboratory settings and readily infect immunocompromised mice. Biomechanical measurements determine that COWP8 is not required for the strength of the oocyst wall. This work confirms the role of cowps in oocyst wall formation and sets a foundation for further exploration of the role of these proteins in transmission of Cryptosporidium parasites.

DOI: https://doi.org/10.1371/journal.ppat.1013561
Cell Death Dis. 2025 Oct 21. 16(1): 743

Deacetylation of TALDO1 by HDAC6 promotes glycolysis and nasopharyngeal carcinoma progression through a moonlighting function.

Xingzhi Peng, Peijun Zhou, Kun Zhang, Likang Chen, Min Tang, Qin Zhou, Jinwu Peng, Lifang Yang.

Aberrant metabolic enzymes drive glucose metabolism reprogramming, which plays a crucial role in tumor malignancy and metastasis. Protein acetylation is one of the key regulatory mechanisms of metabolic enzyme function, yet its precise role requires further clarification. In the present study, we reported that the deacetylation and low expression of transaldolase 1 (TALDO1) mediated by HDAC6 weakened the inhibitory effect of TALDO1 on tumor proliferation and metastasis in nasopharyngeal carcinoma (NPC). Mechanistically, highly expressed HDAC6 induced lysine 7 (K7) deacetylation of TALDO1, which could inhibit SMURF1-mediated K63-linked ubiquitination, thus reducing the protein stability of TALDO1. Notably, TALDO1 deacetylation inhibited its nuclear translocation and interaction with BRCA1, thereby reducing the inhibition of c-Myc transcriptional activation, promoting the expression of HK2/LDHA/PDK1, and further enhancing glycolysis independent of TALDO1 enzyme activity. This research elucidated the regulatory mechanism of TALDO1 from the perspective of acetylation modification, clarified the moonlighting functions of TALDO1 in metabolic reprogramming, and provided novel biomarkers and intervention strategies, such as HDAC inhibitors, for the clinical treatment of NPC.

DOI: https://doi.org/10.1038/s41419-025-08057-2
Nat Commun. 2025 Oct 24. 16(1): 9407

Global comparative structural analysis of responses to protein phosphorylation.

Miguel Correa Marrero, Victor Hugo Mello, Pablo Sartori, Pedro Beltrao.

Post-translational modifications (PTMs), particularly protein phosphorylation, are key regulators of cellular processes, impacting numerous aspects of protein activity. Despite widespread phosphorylation of eukaryotic proteomes, the function of most phosphosites remains unknown. Elucidating the structural mechanisms underlying phosphorylation is crucial for understanding its regulatory roles. Here, we present a comparative structural analysis of phosphorylated and non-phosphorylated proteins taken from the Protein Data Bank (PDB). Our study systematically evaluates how phosphorylation affects backbone conformation, protein dynamics, and mechanical strain. We found that phosphorylation commonly induces small, stabilizing conformational changes through conformational selection and frequently modulates local residue fluctuations, influencing overall protein motion. Notably, a small but significant subset of phosphosites shows mechanical coupling with functional sites, aligning with the domino model of allosteric signal transduction. This work provides a foundation for studying phosphorylation and other PTMs in their structural context, which will guide the rational design of synthetic phosphosites and enable the engineering of PTM-driven regulatory circuits in synthetic biology.

DOI: https://doi.org/10.1038/s41467-025-64116-4
R Soc Open Sci. 2025 Oct;12(10): 250542

Avian malaria and the overlooked metabolic pathways underlying mosquito-Plasmodium interactions.

Luz Garcia-Longoria, Arnaud Berthomieu, O Hellgren, Ana Rivero.

  Avian malaria parasites pose a significant threat to conservation, affecting populations worldwide. Despite this, our understanding of factors influencing the transmission of avian Plasmodium parasites by vectors is limited to the study of mosquito immune responses. However, the complex life cycle of Plasmodium within the vector suggests that non-immune physiological and metabolic pathways may play equally, if not more, crucial roles in determining whether the parasite completes its development and successfully transmits to the next host. We review some of these pathways, uncovering a fragmented and contradictory body of knowledge. Through transcriptomic analysis of infected and uninfected mosquitoes at various stages of infection, we identify differential expression of numerous metabolic pathways that are essential for Plasmodium development. These include genes involved in meeting the parasite's energetic needs, digestive enzymes facilitating midgut barrier traversal, and salivary enzymes enabling blood meal uptake, among others. This suggests that the parasite has evolved mechanisms to modulate these pathways, thereby enhancing and prolonging infection and transmission. Our findings emphasize the need for a broader, integrative approach to better understand the reciprocal selective pressures between malaria parasites and their vectors and to find novel targets for controlling parasite transmission and ultimately improving malaria control strategies.

Keywords:  Culex quinquefasciatus; Plasmodium relictum; RNA-seq; avian malaria; transcriptomic

DOI:  https://doi.org/10.1098/rsos.250542
Commun Biol. 2025 Oct 20. 8(1): 1485

SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.

Zhang Xianhong, Gao Yue, Zhang Yu, Zhang Yichen, Chen Yufei, Pei Xinke, Zhang Jinhui, Wang Yiqi, Du Yitian, Hao Shuailin, Ni Ting.

Protein lysine succinylation is a crucial post-translational modification that regulates nearly all aspects of eukaryotic and prokaryotic cell, including gene transcription, cell metabolism and redox homeostasis. Among them, metabolic disorders caused by dysfunctional post-translational modifications induce aging and aged-related diseases, including cancer. This study quantified the dynamic changes in protein succinylation in response to DNA damage stress induced by etoposide (ETOP) in tumor cells. A total of 4354 lysine succinylation sites on 1259 proteins were identified, many of which have not been previously reported. Bioinformatics analysis revealed that many proteins are involved in the metabolism of nicotinamide adenine dinucleotide phosphate (NADPH) in mitochondria (including MTHFD2). We further found that low activity or depletion of MTHFD2 enhances the degree of TIS in breast cancer cells and decreases their resistance to chemotherapeutic agents. Interestingly, we also found that SIRT5-mediated desuccinylation of MTHFD2 was able to reduce the senescence of breast cancer cells, thereby enhancing their resistance to chemotherapeutic drugs. This effect may explain the poorer prognosis observed in breast cancer patients with high expression levels of SIRT5 or MTHFD2. These systematic analyses provide new insights into targeting succinylation-modified metabolic proteins to enhance TIS, and their combination with senolytics for breast cancer therapy.

DOI: https://doi.org/10.1038/s42003-025-08878-z
Parasite. 2025 ;32 68

Different patterns of Toxoplasma gondii infection epidemiology in the general population, animal contact workers, and blood donors in southeastern China between 2019 and 2023: a cross-sectional study.

Xiaoxiao Wang, Wei Ruan, Wenjie Xu, Hualiang Chen, Jiaqi Zhang, Xuan Zhang, Kegen Yu, Qiaoyi Lu, Zhen Wang, Jimin Sun.

  There are estimated to be over one billion human infections of Toxoplasma gondii worldwide. However, significant spatial heterogeneity exists across countries and regions. For this study, a total of 2,943 participants were enrolled between 2019 and 2023 in Zhejiang Province, southeastern China including 519 animal contact workers, 1,722 people from the general population, and 702 blood donors. Anti-T. gondii IgG and IgM in sera were assessed using an enzyme-linked immunosorbent assay. The overall seroprevalence of IgG and IgM was 4.08% and 0.41%, respectively. IgG positivity was highest in the (50, 60] years age group (5.47%, 29/530), while IgM was found in the (60, 70] years age group (1.21%, 3/247). The general population showed the lowest IgG seroprevalence (1.68%) compared to animal contact workers (10.40%) and blood donors (5.27%) (p < 0.001). Patterns of T. gondii IgG prevalence varied by participant type. Increasing seroprevalence with age was observed among animal contact workers, indicating a cumulative effect, while frequency was highest in the (50, 60] and (30, 40] age groups in the general population and blood donors, respectively. Animal contact workers with two types of animal exposure had higher IgG positivity rates (13.16%) than those with one type (8.50%). Occupational exposure to cattle was associated with the highest frequency of IgG (12.69%), followed by pigs (9.69%), and sheep (8.85%). This study provides critical insights into the epidemiological characteristics of T. gondii infections across distinct population groups in Eastern China.

Keywords:  Animal contact workers; Blood donors; Cross-sectional study; Occupational exposure; Seroprevalence

DOI:  https://doi.org/10.1051/parasite/2025061