bims-toxgon 2025-06-08 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–06–08
23 papers selected by
Lakesh Kumar, BITS Pilani

A Protein Disulfide Isomerase Coordinates Redox Homeostasis and ER Calcium Regulation for Optimal Lytic Cycle Progression in Toxoplasma gondii.
mSphere of Influence: Adapting new models for studying Toxoplasma gondii gut interactions.
Proteolytic processing and host nuclear targeting of the novel effector GRA84 in Toxoplasma gondii.
Special Issue: Who makes the decisions? Uncovering the evolutionary implications and clinical applications of Toxoplasma gondii's Fatal Feline Attraction.
Disruption of Epidermal Growth Factor Receptor Signaling in RPE Cells Increases Resistance to Ocular Toxoplasmosis.
Special Issue: Re-assessing host manipulation in Toxoplasma: the underexplored role of sexual transmission - evidence, mechanisms, implications.
Prophylactic Effect of Microwave Radiation on Toxoplasma gondii Tachyzoites of RH Strain: A Method for Partial Immunization in BALB/c Mice.
Toxoplasma gondii: a parasite pollutant in the Arctic.
Design, synthesis, and biological evaluation of indazole-based histone deacetylase 6 inhibitors.
Effect of histone deacetylases on pancreatic physiology and pathology: a review.
Wastewater-based epidemiology for waterborne protozoa: a comparison of analytical methods for detecting Cryptosporidium spp.
Mapping the Interactions Among Class IIa Histone Deacetylases and Myocyte Enhancer Factor 2s.
SETD2 suppresses tumorigenesis in a KRAS G12C -driven lung cancer model and its catalytic activity is regulated by histone acetylation.
Identification of α-azacyclic acetamide-based inhibitors of P. falciparum Na + pump ( Pf ATP4) with fast-killing asexual blood-stage antimalarial activity by phenotypic screening.
Unlocking the Potential of Histone Deacetylase Inhibitors in Combatting Age-Related Retinal Degenerative Diseases.
The Nuclear Localization of ACLY Guards Early Embryo Development Through Recruiting P300 and HAT1 to Promote Histone Acetylation and Transcription.
Methionine-triggered growth arrest reveals activation of Gcn2 by methionine transporter endocytosis.
Genetic crosses reveal genomic loci responsible for virulence in Cryptosporidium parvum infection.
The Splicing Factor PTBP1 interacts with RUNX1 and is Required for Leukemia Cell Survival.
The mechanism of acetyl-CoA synthase through the lens of a nickel model system.
The Biogeography of Apicomplexan Parasites in Tropical Soils.
Cellular metabolic state controls mitochondrial RNA kinetics.
Polypyrimidine tract binding proteins PTBP1 and PTBP2 associate with distinct proteins and have distinct post-translational modifications in neuronal nuclear extract.

bioRxiv. 2025 May 15. pii: 2025.05.15.654346. [Epub ahead of print]

A Protein Disulfide Isomerase Coordinates Redox Homeostasis and ER Calcium Regulation for Optimal Lytic Cycle Progression in Toxoplasma gondii.

Katherine E Moen, Silvia N J Moreno.

The endoplasmic reticulum (ER) maintains an oxidative environment that facilitates disulfide bond formation, a critical process for proper protein folding. Protein disulfide isomerases (PDIs) are ER resident enzymes that facilitate the formation, breakage, and rearrangement of disulfide bonds between cysteine residues, thereby stabilizing protein structures. Although PDIs are functionally diverse, they all contain at least 1 thioredoxin-like domain and mediate disulfide exchange through their conserved CXXC motifs. The Apicomplexan parasite, Toxoplasma gondii , infects approximately one third of the world population, posing a significant risk to immunosuppressed individuals and unborn fetuses. The fast-replicating tachyzoite form engages in a lytic cycle, causing host tissue damage and contributing to pathogenesis. While approximately 26 PDIs are predicted to be present in T. gondii , their specific roles remain largely unexplored. In this study, we investigate TgPDIA3, a T. gondii PDI localized to the ER, along with several of its interacting protein substrates. We explore its role in ER redox activity and calcium sequestration and assess how these functions contribute to the parasite's lytic cycle.
Importance: The lytic cycle of Toxoplasma gondii is essential to the pathogenesis of toxoplasmosis, with calcium signaling playing a crucial role in driving this process. Cytosolic calcium is tightly regulated through either sequestration into intracellular stores or extrusion from the cell. The ER, likely the largest calcium store in T. gondii , remains poorly characterized. In this study, we identify a link between ER redox regulation and calcium homeostasis and signaling in T. gondii . These findings suggest that redox-controlled calcium homeostasis and flux in the ER is a key driver of the parasite's lytic cycle progression.

DOI: https://doi.org/10.1101/2025.05.15.654346
mSphere. 2025 Jun 06. e0021125

mSphere of Influence: Adapting new models for studying Toxoplasma gondii gut interactions.

Carlos J Ramírez-Flores.

  Carlos J. Ramírez-Flores works in the field of parasitology, focusing on how Toxoplasma gondii crosses host barriers. In this mSphere of Influence article, he reflects on how three papers-by Shim, Kim, and Gregg-built on Dubey's foundational mouse work to reshape his view of the parasite's earliest intestinal events and to inspire his use of gut-on-chip platforms.

Keywords:  3D model; Toxoplasma gondii; host-parasite interaction; intestinal colonization; intracellular parasites; microfluidics

DOI:  https://doi.org/10.1128/msphere.00211-25
Mol Biol Cell. 2025 Jun 04. mbcE24070322

Proteolytic processing and host nuclear targeting of the novel effector GRA84 in Toxoplasma gondii.

Amara C Thind, Andrew J Mead, Justin J Quan, Jihui Sha, James A Wohlschlegel, Peter J Bradley.

Toxoplasma gondii and its relative Neospora caninum are apicomplexan pathogens that secrete an array of dense granule proteins into the parasitophorous vacuole and host cell, where they play roles in acquiring nutrients and modulating host cell functions. Here, we characterize the novel dense granule protein GRA84 in T. gondii and N. caninum, which is secreted into the parasitophorous vacuole and exported into the host cell nucleus. Disruption of Toxoplasma GRA84 does not affect in vitro parasite replication or establishment or maintenance of the chronic infection in vivo. We show that this effector uses the MYR translocon to traverse the vacuolar membrane and is dependent on the aspartyl protease ASP5 for its export to the host nucleus. We demonstrate that GRA84 undergoes processing which removes over 90 amino acids from its N-terminus, an event that is independent of ASP5. We also use mutagenesis to disrupt processing and show that maturation is critical for transit across the vacuolar membrane. Taken together, this work identifies GRA84 in both T. gondii and N. caninum and reveals an unusual processing event that is necessary for maturation of the protein and export of the effector into the host cell.

DOI: https://doi.org/10.1091/mbc.E24-07-0322
Folia Parasitol (Praha). 2025 May 30. pii: 2025.016. [Epub ahead of print]72

Special Issue: Who makes the decisions? Uncovering the evolutionary implications and clinical applications of Toxoplasma gondii's Fatal Feline Attraction.

Joanne P Webster.

  Here I recount my research journey on the coccidian protist Toxoplasma gondii (Nicolle et Manceaux, 1908), a ubiquitous parasite capable of infecting all warm-blooded animals as intermediate or secondary host, but with only members of the Felidae as its definitive host. I describe my initial studies into its epidemiology and persistence within the UK, and how this led on to a series of biologically and ethically appropriate studies into T. gondii's apparent specific manipulation of its rat intermediate host to facilitate transmission to its feline definitive host. I then describe how this prompted searches into the potential mechanisms of action behind such manipulation and what this raises in terms of behavioural changes, from the subtle to severe, across other secondary hosts including humans.

Keywords:  Toxoplasmosis; behaviour; definitive host; intermediate host; manipulation; rats

DOI:  https://doi.org/10.14411/fp.2025.016
Invest Ophthalmol Vis Sci. 2025 Jun 02. 66(6): 11

Disruption of Epidermal Growth Factor Receptor Signaling in RPE Cells Increases Resistance to Ocular Toxoplasmosis.

Amelia Pfaff, Alyssa Hubal, Sarah Vos, Vera Bonilha, Carlos S Subauste.

Purpose: The in vivo role of RPE cells in ocular toxoplasmosis is poorly understood. Toxoplasma gondii activates Epidermal growth factor receptor (EGFR) to avoid autophagic killing. We examined the in vivo role of RPE using mice with dominant negative (DN) EGFR in RPE. We examined whether EGFR blockade in RPE increased resistance to ocular toxoplasmosis, induced autophagy-dependent killing of T. gondii, and modulated retinal invasion by T. gondii.
Methods: We bred mice expressing tetracycline-repressible transactivator under the control of MART-1 (RPE promotor) with mice expressing the tetracycline operator upstream of DN EGFR. Mice were infected with T. gondii tissue cysts. Histopathology and T. gondii B1 gene expression (qPCR) were examined. Retinal invasion by T. gondii was examined after intravenous challenge with the parasite. RPE were infected with T. gondii tachyzoites followed by assessment of parasite load and expression of LC3 and LAMP-1 (immunofluorescence).
Results: Mice with DN EGFR in RPE exhibited lower parasite load and histopathology that became evident at 4 weeks post infection. No difference in parasite load was noted during hematogenous invasion of the retina by T. gondii. RPE with DN EGFR exhibited spontaneous recruitment of LC3 and LAMP-1 around intracellular parasites and toxoplasmacidal activity that was dependent on the autophagy protein ULK-1 and lysosomal enzymes.
Conclusions: DN EGFR in the RPE increases resistance against ocular toxoplasmosis, an effect that would occur after retinal invasion by T. gondii. Protection is accompanied by autophagic killing of T. gondii in RPE. This report provides the first evidence that RPE can protect against ocular toxoplasmosis.

DOI: https://doi.org/10.1167/iovs.66.6.11
Folia Parasitol (Praha). 2025 May 20. pii: 2025.015. [Epub ahead of print]72

Special Issue: Re-assessing host manipulation in Toxoplasma: the underexplored role of sexual transmission - evidence, mechanisms, implications.

Ashkan Latifi, Jaroslav Flegr, Sarka Kankova.

  Latent infection with Toxoplasma gondii (Nicolle et Manceaux, 1908) has been repeatedly correlated with behavioural and physiological changes in both humans and animals. While classically regarded as a parasite transmitted via ingestion or vertical (transplacental) transmission, accumulating evidence suggests that sexual transmission may also contribute to its epidemiology. This review explores the hypothesis that some behavioural effects of toxoplasmosis - especially those related to attraction, sexual activity, and mate choice - may have evolved to facilitate sexual transmission of the parasite. We summarise findings from animal models and human studies that show modified sexual preferences, altered sexual activity, enhanced attractiveness in infected individuals, and elevated prevalence of T. gondii in groups exhibiting high sexual activity or non-traditional sexual behaviour patterns. Particular attention is given to the role of testosterone, which may mediate both behavioural changes and reproductive consequences, such as shifts in offspring sex ratios and fertility outcomes. Direct detection of the parasite in semen and evidence of transmission through insemination in non-human species further support the plausibility of this route. The observed behavioural effects may also intersect with mechanisms previously thought to enhance predation risk, such as altered fear responses to felid odours. Taken together, these findings point to the possibility that sexual transmission, while likely secondary in humans, may have played a more substantial role in the evolutionary history and current ecology of T. gondii than previously appreciated. This perspective also provides an alternative interpretative framework for understanding the broad spectrum of phenotypic changes associated with latent toxoplasmosis. Further interdisciplinary research is required to clarify the relative contribution of sexual transmission to the parasite's life cycle and to assess its implications for public health and theory of host-parasite coevolution.

Keywords:  manipulation; parasite manipulation.; review; sexual behaviour; sexually transmitted diseases; testosterone; toxoplasmosis

DOI:  https://doi.org/10.14411/fp.2025.015
J Parasitol Res. 2025 ;2025 1666892

Prophylactic Effect of Microwave Radiation on Toxoplasma gondii Tachyzoites of RH Strain: A Method for Partial Immunization in BALB/c Mice.

Amin Shamsaei, Iraj Mohammadpour, Zahra Mohammadi, Qasem Asgari.

  Toxoplasma gondii is a ubiquitous protozoan parasite causing toxoplasmosis in humans. The goal of this study was to examine the effect of microwave on the viability and infectivity of T. gondii tachyzoites of the RH strain, both in vitro and in vivo. T. gondii tachyzoites of the RH strain were treated with microwave radiation for 5, 10, 15, and 20 s. The viability of treated tachyzoites was assessed using flow cytometry. The in vitro infectivity of these treated tachyzoites was investigated using the HeLa cell culture. For in vivo studies, BALB/c mice received two injections of treated tachyzoites mixed with Freund's adjuvant, over a fortnight interval, and their daily survival rates were monitored. Subsequently, untreated tachyzoites were inoculated into surviving mice in order to evaluate induced immunity. The produced IgG antibody titers in surviving mice were measured using the modified agglutination test. The flow cytometry method showed mortality rates of 46.89%, 74.11%, 88.38%, and 99.34% for the treated tachyzoites at 5, 10, 15, and 20 s, respectively. An in vitro analysis showed no proliferation of treated tachyzoites at 10- to 20-s time points after 24, 48, and 72 h. An in vivo study showed that all mice injected with tachyzoites treated for 5 s died, while those treated for 10-20 s survived. Mice that survived were exposed to untreated tachyzoites and showed a significant viability rate up to 18 days. The modified agglutination test showed an antibody titer of 1:80 in partially immunized mice. These results suggest that microwave-treated tachyzoites combined with Freund's adjuvant greatly enhance survival rates, reduce infectivity, and induce a humoral immune response in mice, offering partial protection against acute toxoplasmosis.

Keywords:  MAT; Toxoplasma gondii; flow cytometry; infectivity; microwave; survivability

DOI:  https://doi.org/10.1155/japr/1666892
Trends Parasitol. 2025 Jun 04. pii: S1471-4922(25)00128-X. [Epub ahead of print]

Toxoplasma gondii: a parasite pollutant in the Arctic.

Emily Jenkins, Émilie Bouchard, Adrián Hernández-Ortiz.

  It is enigmatic, but important, to understand how Toxoplasma gondii, with felids as the ultimate source, enters and circulates among wildlife, people, and the environment of the Arctic, where felids are rare. Informed by studies in the last 15 years, we opine that: (i) marked regional differences in human seroprevalence across the North American Arctic are supported by more numerous animal sentinel studies; (ii) tissue cysts in migratory geese and oocysts shed by felids travel north as 'parasite pollutants' into Arctic ecosystems, moving from land to sea and back again; and (iii) exposure to T. gondii is increasing in polar bears, linked to increased time on land and climate change in the most rapidly warming region of the globe.

Keywords:  Indigenous; One Health; climate change; sentinel; wildlife; zoonotic

DOI:  https://doi.org/10.1016/j.pt.2025.05.003
Eur J Med Chem. 2025 May 22. pii: S0223-5234(25)00550-1. [Epub ahead of print]295 117785

Design, synthesis, and biological evaluation of indazole-based histone deacetylase 6 inhibitors.

Khan Hashim Ali, Sunil K Gupta, Yong Jin Oh, Mosharof Hossain, Ji Hyun Kim, Sun You Park, Young Ho Seo.

  Histone deacetylases (HDACs) have been explored as anticancer targets for over two decades, with six HDAC inhibitors approved for clinical use. However, these pan-HDAC inhibitors exhibit off-target effects, necessitating the development of isoform-selective inhibitors. Among HDACs, HDAC6 has garnered attention due to its dual catalytic domains, cytoplasmic localization, and zinc-finger ubiquitin-binding domain (Zf-UBD). Its role in gene expression, proliferation, protein homeostasis, and cell cycle regulation make it an attractive anticancer target. Here, we report on the design and synthesis of indazole-based HDAC6 inhibitors and evaluate the impact of zinc-binding group (ZBG) modifications on pharmacokinetics. Compound 5j emerged as a selective and potent HDAC6 inhibitor (IC50 = 1.8 ± 0.3 nM), exhibiting strong antiproliferative activity against HCT116 cells (GI50 = 3.1 ± 0.6 μM). It preferentially induced α-tubulin acetylation over histone H3 at concentrations as low as 0.5 μM which is a hallmark of HDAC6 selective inhibition. However, its hydroxamic acid-based ZBG resulted in a very low oral bioavailability (1.2 %). To address this limitation, compound 12 was synthesized with an ethyl hydrazide ZBG, significantly improving oral bioavailability (53 %). These findings highlight compound 12 as a promising lead for further pharmacophore optimization, paving the way for clinically viable HDAC6 selective inhibitors with enhanced drug-like properties.

Keywords:  Anticancer; Epigenetics; Histone deacetylase 6; Indazole; Pharmacokinetics; Small molecule

DOI:  https://doi.org/10.1016/j.ejmech.2025.117785
Int J Biol Macromol. 2025 Jun 01. pii: S0141-8130(25)05389-9. [Epub ahead of print]318(Pt 1): 144837

Effect of histone deacetylases on pancreatic physiology and pathology: a review.

Xinran Song, Xiaofeng Wu, Jun Yang, Ran Xue.

  The incidence of pancreatic diseases is increasing worldwide. Thus, there is a need to develop novel therapeutic strategies and identify molecular targets for pancreatic diseases. Histone deacetylases (HDACs), which are involved in epigenetic regulation, mediate diverse physiological functions and regulate various vital activities in the pancreas. This review examines the roles of HDACs in different pancreatic cells and the potential therapeutic value of targeting HDACs in pancreatic diseases. Additionally, the potential of HDAC inhibitors as a combination therapy strategy for pancreatic diseases has been discussed, providing novel insights and directions for the diagnosis, treatment, and prevention of pancreatic diseases.

Keywords:  Cell biology; Histone deacetylases; Insights; Pancreas; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144837
Sci Total Environ. 2025 Jun 04. pii: S0048-9697(25)01430-5. [Epub ahead of print]987 179789

Wastewater-based epidemiology for waterborne protozoa: a comparison of analytical methods for detecting Cryptosporidium spp.

Pablo Puchades-Colera, Inés Girón-Guzmán, Azahara Díaz-Reolid, Gloria Sánchez, Alba Pérez-Cataluña.

  Cryptosporidium spp., Giardia intestinalis, and Toxoplasma gondii are waterborne pathogens of public health significance. Wastewater-based epidemiology (WBE) has been proposed as an epidemiological tool for monitoring parasites. Although several studies have used standardized methods to detect these parasites in drinking and surface water, they are not always suitable for wastewater analysis. In this study, two different extraction protocols and five concentration methods for Cryptosporidium spp. were evaluated using wastewater spiked with C. parvum oocysts. The aluminium-based adsorption-precipitation method, combined with three freeze-thaw cycles and a magnetic-beads-based nucleic acid extraction, proved to be the most efficient, achieving qPCR detection limits of 1.29 × 104 oocysts/L for the selected molecular targets. Levels of Cryptosporidium spp., C. parvum, C. hominis, G. intestinalis, and T. gondii were assessed in wastewater samples from a hospital sewer and a wastewater treatment plant (WWTP) using the optimized procedure. A higher prevalence of T. gondii (46.67 %) was observed in hospital wastewater, followed by C. parvum and C. hominis (13.33 %), with levels ranging from 2.56 to 4.04 Log10 genome copies (gc)/L, 4.86 to 5.17 Log10 gc/L and 4.77 to 5.16 Log10 gc/L, respectively. In samples from the analysed WWTP, the prevalence of C. parvum and T. gondii was similar (52.38 % and 47.62 %, respectively), with levels ranging from 3.60 to 4.87 Log10 gc/L and from 2.49 to 3.77 Log10 gc/L, respectively. Our study provides a feasible protocol for the analysis of Cryptosporidium and Toxoplasma, supporting the use of WBE for the surveillance of parasites transmitted through contaminated water and food.

Keywords:  Cryptosporidium spp.; Giardia intestinalis; Toxoplasma gondii; Wastewater-based epidemiology; qPCR

DOI:  https://doi.org/10.1016/j.scitotenv.2025.179789
J Chem Inf Model. 2025 Jun 06.

Mapping the Interactions Among Class IIa Histone Deacetylases and Myocyte Enhancer Factor 2s.

Narayan Gautam, Sophia Wang, Aykut Üren, Prem P Chapagain, Narayan P Adhikari, Purushottam B Tiwari.

Myocyte enhancer factor 2 (MEF2) transcription factors regulate several developmental programs, including the control of neural crest development and neuronal differentiation as well as survival. MEF2s are highly expressed in cerebellar granule neurons. Class IIa histone deacetylases (HDACs), abundantly expressed in the brain as well, repress gene expression activity of MEF2 via physical interactions and play a critical role in neuronal apoptosis. In this work, we conducted molecular dynamics (MD) simulation-based investigations to investigate interactions among different class IIa HDACs (HDAC4, HDAC5, HDAC7, and HDAC9) and MEF2s (MEF2A, MEF2B, MEF2C, and MEF2D). Our results show that hydrophobic interactions are the main mechanism for the formation of class IIa HDAC-MEF2 complexes. Our analysis shows that L66 and L67 in all MEF2s mostly contribute to the hydrophobic interactions. All residues that establish hydrophobic interactions, hydrogen bonding, and salt bridges are conserved in all MEF2s. Calculations of the MM/GBSA binding free energies also show that the class IIa HDAC-MEF2 complexes exhibit comparable binding affinities. We performed surface plasmon resonance (SPR)-based direct binding experiments using four different purified class IIa HDACs and MEF2A to validate our computational investigations. The SPR results confirmed the direct binding between the class IIa HDACs and MEF2A with fairly comparable nanomolar affinity (3.5 nM to 19.1 nM). This is a comprehensive study to map interactions among class IIa HDACs and MEF2s. We believe that our investigation offers the scientific community valuable insights to further understand, explore, and investigate biomolecular systems that include the class IIa HDAC-MEF2 complex formations.

DOI: https://doi.org/10.1021/acs.jcim.5c00858
bioRxiv. 2025 May 18. pii: 2025.05.16.654513. [Epub ahead of print]

SETD2 suppresses tumorigenesis in a KRAS G12C -driven lung cancer model and its catalytic activity is regulated by histone acetylation.

Ricardo J Mack, Natasha M Flores, Geoffrey C Fox, Hanyang Dong, Metehan Cebeci, Simone Hausmann, Tourkian Chasan, Jill M Dowen, Brian D Strahl, Pawel K Mazur, Or Gozani.

Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiologic and pathologic processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that SETD2 functions as a potent tumor suppressor in a KRAS G12C -driven lung adenocarcinoma (LUAD) mouse model, and that acetylation at H3K27 (H3K27ac) enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo , SETD2 ablation accelerates lethality in an autochthonous KRAS G12C -driven LUAD mouse tumor model. Biochemical analyses reveal that polyacetylation of histone tails in a nucleosome context promote H3K36 methylation by SETD2. In addition, monoacetylation exerts position-specific effects to stimulate SETD2 methylation activity. In contrast, mono-ubiquitination at various histone sites, including at H2AK119 and H2BK120, does not affect SETD2 methylation of nucleosomes. Together, these findings provide insight into how SETD2 integrates histone modification signals to regulate H3K36 methylation and highlights the potential role of SETD2-associated epigenetic crosstalk in cancer pathogenesis.

DOI: https://doi.org/10.1101/2025.05.16.654513
bioRxiv. 2025 May 23. pii: 2025.05.20.655166. [Epub ahead of print]

Identification of α-azacyclic acetamide-based inhibitors of P. falciparum Na + pump ( Pf ATP4) with fast-killing asexual blood-stage antimalarial activity by phenotypic screening.

Arturo Casas, Leah S Imlay, Vandana Thathy, Kate J Fairhurst, Adele M Lehane, Aloysus K Lawong, Ionna Deni, Josefine Striepen, Seungheon Lee, Ashwani Kumar, Chao Xing, Hanspeter Niederstrasser, Bruce A Posner, Benoît Laleu, Susan A Charman, David A Fidock, Joseph M Ready, Margaret A Phillips.

Malaria treatments are compromised by drug resistance, creating an urgent need to discover new drugs. We used a phenotypic high-throughput screening (HTS) platform to identify new antimalarials, uncovering three related pyrrole-, indole-, and indoline-based series with a shared α-azacyclic acetamide core. These compounds showed fast-killing activity on asexual blood-stage Plasmodium falciparum parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na + regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the P. falciparum Na + pump ( Pf ATP4). Pf ATP4 is localized to the parasite plasma membrane and is essential for maintaining a low cytosolic Na + concentration. Resistance selections on P. falciparum parasites with two α-azacyclic acetamide analogs identified mutations in Pf ATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming Pf ATP4 as the target. Pf ATP4 is a well-established antimalarial target, and identification of additional Pf ATP4 inhibitors provides alternative avenues to disrupt its function.

DOI: https://doi.org/10.1101/2025.05.20.655166
Ageing Res Rev. 2025 May 31. pii: S1568-1637(25)00134-5. [Epub ahead of print] 102788

Unlocking the Potential of Histone Deacetylase Inhibitors in Combatting Age-Related Retinal Degenerative Diseases.

Bo Liu, Minglu Wang, Ning Pu, Jiale Wang, Wenhui Fan, Chengkang Qu, Hao Wu, Zongming Song, Ye Tao.

  Retinal degeneration (RD), a group of progressive diseases marked by the loss of retinal neurons. Aging contributes to the gradual decline in cellular function, which, in turn, exacerbates the pathogenesis of RD through complex molecular mechanisms, including aberrant gene expression, impaired cellular signaling pathways, oxidative stress, and inflammation. The pivotal role of epigenetic histone modifications in mediating the onset and progression of neurological disorders has garnered increasing attention, especially concerning histone acetylation. The level of histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs can enzymatically modify lysine residues on histones or non-histones via adding or removing acetyl groups, leading to changes in transcriptional activity. Histone deacetylase inhibitors (HDACis) can interfere with the deacetylase activity of HDACs, enhance the level of both histone and non-histone acetylation, and exert a regulatory influence on gene transcription. Accumulating evidence supports the role of HDACis in the treatment of multiple medical conditions beyond cancer, renewing interest in their potential applications in age-related diseases. In this context, HDAC inhibition represents a novel approach for mitigating the age-related cellular dysfunctions contributing to RD. HDACis hold promise in addressing these pathological processes and preserving retinal function through targeting HDACs. We intend to elucidate the neuroprotective effects of common HDACis on age-related RD, with a focus on their role in counteracting the detrimental effects of aging, and provide a comprehensive summary of the efficacy of HDACis in both animal models and clinical trials for age-related RD. These findings would enrich our understanding of HDACis and promote their future applications in the treatment of age-related RD.

Keywords:  Aging; Epigenetics; Histone deacetylase inhibitors; Retinal degeneration; Visual function

DOI:  https://doi.org/10.1016/j.arr.2025.102788
Adv Sci (Weinh). 2025 Jun 05. e14367

The Nuclear Localization of ACLY Guards Early Embryo Development Through Recruiting P300 and HAT1 to Promote Histone Acetylation and Transcription.

Yerong Ma, Yingyi Zhang, Weijie Yang, Xiaomei Tong, Siya Liu, Yan Zhou, Mengjia Qiu, Huifang Jiang, Zhanhong Hu, Peipei Ren, Yan Rong, Mengru Lai, Jiamin Jin, Fei Huang, Liujian Ouyang, Feng Zhou, Heng-Yu Fan, Yin-Li Zhang, Songying Zhang.

  Metabolic processes and epigenetic reprogramming are intricately interconnected; however, their mechanistic interplay remains unclear. This study elucidates the role of ATP-citrate lyase (ACLY), an essential enzyme in acetyl-CoA production that uniquely localizes to the nucleus in oocytes and early embryos. Maternal Acly deletion in oocytes preserves fertility due to the compensatory upregulation of Acetyl-CoA Synthetase 2 (ACSS2), whereas zygotic Acly knockout causes developmental arrest at the pre-blastocyst stage without ACSS2 induction. Mechanistically, nuclear ACLY recruits and interacts with histone acetyltransferases, specifically E1A binding protein p300 (P300) and histone acetyltransferase 1 (HAT1), supplying acetyl-CoA for histone acetylation to activate transcription, which is essential for embryogenesis. Clinically, enhanced ACLY nuclear localization correlates with superior quality of human embryos. Functionally, AKT-mediated phosphorylation (Thr447/Ser451/Ser455) drives the nuclear translocation of ACLY and facilitates its interaction with HAT1 and P300. Inhibition of ACLY or its phosphorylation disrupts the promoting effects of AKT activators, such as insulin-like growth factor-1 (IGF-1), on blastocyst formation. These findings suggest that ACLY is a metabolic hub that bridges signaling and epigenetic remodeling, ensuring acetyl-CoA availability for chromatin modifications, and offering insights into the metabolic determinants of embryo viability and potential therapeutic targets for infertility.

Keywords:  ACLY; HAT1; P300; early embryo development; histone acetylation

DOI:  https://doi.org/10.1002/advs.202414367
bioRxiv. 2025 May 14. pii: 2025.05.12.653625. [Epub ahead of print]

Methionine-triggered growth arrest reveals activation of Gcn2 by methionine transporter endocytosis.

Nathaniel L Hepowit, Hayley L Singkhek, Derek J Johnson, Jason A MacGurn.

Cell growth checkpoints require coordination between multiple sensing and signaling systems to ensure that cells only proceed with growth and division when conditions are favorable and adequate resources are available. This coordination between nutrient sensing and growth signaling is fundamental to understanding how nutrient supply regulates the cellular metabolic economy. Much of our current understanding is driven by studies that examine the cellular response to nutrient deprivation. For example, TORC1 activity promotes cell growth when amino acids are available, but amino acid deprivation decreases TORC1 activity resulting in activation of catabolic activities. In this study, we examine how cells respond to stimulation with excess amino acids. We report that stimulation with excess Ile, Phe and Met slows cell growth and triggers a G1 cell cycle arrest. Similar to a starvation response, surplus Ile, Phe and Met induce autophagy and trigger decreased TORC1 activity. In the case of stimulation with excess Met, the Gcn2 pathway is required for growth arrest, autophagy induction, and TORC1 dampening. Unexpectedly, Gcn2 is activated by stimulation with excess Met, and this activation requires endocytosis of the methionine transporter Mup1. These results indicate that endocytosis of an amino acid transporter is required to activate the Gcn2 pathway, providing an example for how nutrient transporter trafficking may function as a sensor contributing to cell growth control.

DOI: https://doi.org/10.1101/2025.05.12.653625
bioRxiv. 2025 May 21. pii: 2025.05.20.655157. [Epub ahead of print]

Genetic crosses reveal genomic loci responsible for virulence in Cryptosporidium parvum infection.

Sebastian Shaw, Xue Li, Gracyn Buenconsejo, Tiffany H Zhou, Allison Cohen, Daniel Yasur-Landau, Rui Xiao, Daniel P Beiting, Timothy J C Anderson, Boris Striepen.

The relationship between parasite genotype and pathogenesis is largely unknown for Cryptosporidium , a leading cause of diarrheal disease in children. An array of parasites with similar genomes produces varied disease outcomes in different hosts. Here, we isolate and characterize Cryptosporidium parvum strains that show marked differences in virulence and persistence in mice. Taking advantage of the sexual lifecycle of this eukaryotic pathogen, we use genetic crosses to discover the underlying chromosomal loci. Whole-genome sequencing and bulk segregant analysis of infection selected progeny mapped three loci on chromosomes 2, 6, and 7 associated with the ability to colonize and persist in mice and the positions of drug resistance genes. The chromosome 6 locus encodes the hyper-polymorphic surface glycoprotein GP60. Reverse genetic studies in both parental strains demonstrate that GP60 controls parasite burden and virulence, but not persistence, and reveal the dominance of the less virulent allele, suggesting it restricts virulence.

DOI: https://doi.org/10.1101/2025.05.20.655157
bioRxiv. 2025 May 21. pii: 2025.05.16.654547. [Epub ahead of print]

The Splicing Factor PTBP1 interacts with RUNX1 and is Required for Leukemia Cell Survival.

Arjun Dhir, Alexander Ethell, Riley Watkins, Calvin Lam, Kevin Tur-Rodriguez, Jimmie Persinger, Kasidy K Dobish, Sipra Panda, Shannon M Buckley, Samantha A Swenson, Sandipan Brahma, M Jordan Rowley, R Katherine Hyde.

Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1 dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival.
KEY POINTS: PTBP1 binds RUNX1 in a HDAC1-dependent manner and co-localizes to the promoters of target genes in leukemia cells.Loss of PTBP1 decreases expression of key metabolic genes, resulting in decreased cell growth and glycolysis, increased sensitivity to chemotherapy, and cell death.

DOI: https://doi.org/10.1101/2025.05.16.654547
Nat Commun. 2025 Jun 04. 16(1): 5177

The mechanism of acetyl-CoA synthase through the lens of a nickel model system.

Shounak Nath, Leonel Griego, Liviu M Mirica.

Given the urgent need to develop new methods of CO2/CO utilization, understanding the mechanism of acetyl-CoA synthase (ACS)-a primordial nickel-containing enzyme that converts these gases into a source of cellular energy-is crucial; however, conflicting hypotheses and a dearth of well-characterized bioorganometallic intermediates have hindered a proper understanding of its mechanism. Herein, we report a functional model system that supports several organometallic intermediates proposed for ACS, including the long sought-after Ni(methyl)(CO) species, and promotes all key reaction steps during catalysis: methylation, carbonylation, and thiolysis. Our investigations provide the following key mechanistic insights that are directly relevant to ACS: (i) the binding of a second CO molecule to the Ni center promotes migratory insertion, (ii) both paramagnetic and diamagnetic Ni intermediates are involved, (iii) one-electron oxidation of the NiII(acetyl)(thiolate) species drives a fast reductive elimination, and (iv) a random binding order of the methyl and CO groups to the Ni center is feasible.

DOI: https://doi.org/10.1038/s41467-025-60163-z
Ecol Evol. 2025 Jun;15(6): e71478

The Biogeography of Apicomplexan Parasites in Tropical Soils.

Rachel M Shepherd, Angela M Oliverio.

  Parasitic protists such as Apicomplexa, an abundant group of soil protists, contribute to ecosystem processes and nutrient cycling in belowground soil systems through their obligate symbioses with soil Metazoa. Yet despite the importance of soil parasites, the biodiversity and biogeography of Apicomplexa in belowground systems remain poorly characterized. Leveraging 205 soils collected across a rainfall gradient spanning the isthmus of Panama, we sought to understand the distribution of soil Apicomplexa lineages and how abiotic (e.g., soil and climatic) and biotic (e.g., soil Metazoa) factors relate to their diversity and structure. Apicomplexa were highly heterogeneous across the samples and comprised 30% of the soil protist community on average. Soil pH, along with phosphorus and magnesium, best explained the overall distribution of Apicomplexa. Soil Metazoa distributions also corresponded to Apicomplexa distributions, and many Metazoan taxa co-occurred with particular Apicomplexa, which may reflect ecological interactions (such as parasitism) or shared habitat preferences. These results highlight the potential roles of both soil and climatic variables and putative hosts in structuring parasite distributions in belowground tropical systems. Our work builds a broader understanding of Apicomplexa biodiversity in tropical soils and sheds light on environmental factors that may contribute to shaping their distribution in belowground systems. These results help inform our understanding of the importance of parasites in tropical forest soils.

Keywords:  Apicomplexa; microbial eukaryotes; parasites; protists; soil biogeography; soil microbial ecology

DOI:  https://doi.org/10.1002/ece3.71478
bioRxiv. 2025 May 27. pii: 2025.05.13.653903. [Epub ahead of print]

Cellular metabolic state controls mitochondrial RNA kinetics.

Sean D Reardon, Clarisa Bautista, Shannon C Cole, Julien Cicero, Tatiana V Mishanina.

Human mitochondrial genome encodes essential genes for the oxidative phosphorylation (OXPHOS) complexes. These genes must be transcribed and translated in coordination with nuclear-encoded OXPHOS components to ensure correct stoichiometry during OXPHOS complex assembly in the mitochondria. While much is known about nuclear gene regulation during metabolic stresses like glucose deprivation, little is known about the accompanying transcriptional response in mitochondria. Using microscopy, roadblocking qPCR, and transcriptomics, we studied mitochondrial transcription in cells subjected to glucose deprivation, which is known to cause nuclear transcription downregulation and to activate the integrated stress response (ISR). We found that glucose deprivation stabilizes mitochondrial RNAs and slows mitochondrial transcription, effects that are quickly reversed with glucose reintroduction. Although transcriptomics revealed strong upregulation of the ISR, mitochondrial RNA stabilization was not upregulated by pharmacological activation of the ISR, but was promoted by inhibition of glycolysis, unveiling a direct connection between metabolism and regulation of mitochondrial gene expression.

DOI: https://doi.org/10.1101/2025.05.13.653903
PLoS One. 2025 ;20(6): e0325143

Polypyrimidine tract binding proteins PTBP1 and PTBP2 associate with distinct proteins and have distinct post-translational modifications in neuronal nuclear extract.

Michael E Sullivan, Jacob A Edberg, Christopher I Nunez, Herbert L Axelrod, Niroshika M Keppetipola.

RNA binding proteins play an important role in regulating alternative pre-mRNA splicing and in turn cellular gene expression. Polypyrimidine tract binding proteins, PTBP1 and PTBP2, are paralogous RNA binding proteins that play a critical role in the process of neuronal differentiation and maturation; changes in the concentration of PTB proteins during neuronal development direct splicing changes in many transcripts that code for proteins critical for neuronal differentiation. PTBP1 can compensate for the loss of PTBP2 in some developmental contexts but not others signifying the paralogs have distinct functions. How two highly structurally similar proteins regulate different sets of neuronal exons is unclear and if known, will reveal how gene families evolved to achieve tissue-specific splicing and in turn, gene expression patterns. Here, we incubated PTBP1 and PTBP2 under splicing reaction conditions containing neuronal WERI retinoblastoma nuclear extract and probed for interacting partner proteins and chemical modifications via mass spectrometry. Our results reveal key differences in the kinds of proteins and processes the paralogs associate with under these conditions. Our data also highlight the presence of novel and distinct chemical modifications on the paralogs when incubated with neuronal nuclear extracts. Collectively, our study suggests a role for chemical modifications in regulating PTBP function in neuronal vs non-neuronal cells.

DOI: https://doi.org/10.1371/journal.pone.0325143