bims-toxgon 2023-12-17 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2023–12–17
eightteen papers selected by
Lakesh Kumar, BITS Pilani

The splicing factor SR2 is an important virulence factor of Toxoplasma gondii.
The Toxoplasma protein phosphatase 6 catalytic subunit (TgPP6C) is essential for cell cycle progression and virulence.
In vitro production of cat-restricted Toxoplasma pre-sexual stages.
Susceptibility of Toxoplasma gondii to autophagy in human cells relies on multiple interacting parasite loci.
Functional and biochemical characterisation of the Toxoplasma gondii succinate dehydrogenase complex.
A candidate virulence factor of Eimeria tenella (EtROP30) predicted by virulence enhancement of transgenic Toxoplasma gondii.
Toxoplasma gondii-induced neutrophil extracellular traps are relevant to glycolysis, TLR2, and TLR4 MAPK signaling pathway in goats.
Gut microbiota-related metabolite alpha-linolenic acid mitigates intestinal inflammation induced by oral infection with Toxoplasma gondii.
Histone globular domain epigenetic modifications: The regulators of chromatin dynamics in malaria parasite.
Cat parasite Toxoplasma tricked to grow in a dish.
Toxoplasma gondii seroprevalence in reindeer (Rangifer tarandus tarandus L.) in northern Sweden: a cross-sectional study from 2014.
Lentinan has a beneficial effect on cognitive deficits induced by chronic Toxoplasma gondii infection in mice.
The patatin-like phospholipase PfPNPLA2 is involved in the mitochondrial degradation of phosphatidylglycerol during Plasmodium falciparum blood stage development.
HDAC1: An Essential and Conserved Member of the Diverse Zn2+-Dependent HDAC Family Driven by Divergent Selection Pressure.
Discovery of YSR734: A Covalent HDAC Inhibitor with Cellular Activity in Acute Myeloid Leukemia and Duchenne Muscular Dystrophy.
The dark side of SIRT7.
O-GlcNAcylation: the sweet side of epigenetics.
Current HDAC Inhibitors in Clinical Trials.

Front Microbiol. 2023 ;14 1302512

The splicing factor SR2 is an important virulence factor of Toxoplasma gondii.

Xiao-Jing Wu, Jin Gao, Xiao-Nan Zheng, Hany M Elsheikha, Ting-Ting Li, Yong-Jie Kou, Meng Wang, Xing-Quan Zhu.

  Serine/arginine-rich (SR) proteins are key factors with important roles in constitutive and alternative splicing (AS) of pre-mRNAs. However, the role of SR splicing factors in the pathogenicity of T. gondii remains largely unexplored. Here, we investigated the role of splicing factor SR2, a homolog of Plasmodium falciparum SR1, in the pathogenicity of T. gondii. We functionally characterized the predicted SR2 in T. gondii by gene knockout and studied its subcellular localization by endogenous protein HA tagging using CRISPR-Cas9 gene editing. The results showed that SR2 was localized in the nucleus and expressed in the tachyzoite and bradyzoite stages. In vitro studies including plaque formation, invasion, intracellular replication, egress and bradyzoite differentiation assays showed that deletion of SR2 in type I RH strain and type II Pru strains had no significant effect on the parasite growth and bradyzoite differentiation (p > 0.05). Interestingly, the disruption of SR2 in RH type I (p < 0.0001) and Pru type II (p < 0.05) strains resulted in varying degrees of attenuated virulence. In addition, disruption of SR2 in type II Pru strain significantly reduced brain cyst burden by ~80% (p < 0.0001). Collectively, these results suggest that splicing factor SR2 is important for the pathogenicity of T. gondii, providing a new target for the control and treatment of toxoplasmosis.

Keywords:  CRISPR-Cas9; SR proteins; Toxoplasma gondii; alternative splicing; pathogenicity; splicing factor SR2

DOI:  https://doi.org/10.3389/fmicb.2023.1302512
PLoS Pathog. 2023 Dec 13. 19(12): e1011831

The Toxoplasma protein phosphatase 6 catalytic subunit (TgPP6C) is essential for cell cycle progression and virulence.

Qin-Li Liang, Lan-Bi Nie, Hany M Elsheikha, Ting-Ting Li, Li-Xiu Sun, Zhi-Wei Zhang, Meng Wang, Bao-Quan Fu, Xing-Quan Zhu, Jin-Lei Wang.

Protein phosphatases are post-translational regulators of Toxoplasma gondii proliferation, tachyzoite-bradyzoite differentiation and pathogenesis. Here, we identify the putative protein phosphatase 6 (TgPP6) subunits of T. gondii and elucidate their role in the parasite lytic cycle. The putative catalytic subunit TgPP6C and regulatory subunit TgPP6R likely form a complex whereas the predicted structural subunit TgPP6S, with low homology to the human PP6 structural subunit, does not coassemble with TgPP6C and TgPP6R. Functional studies showed that TgPP6C and TgPP6R are essential for parasite growth and replication. The ablation of TgPP6C significantly reduced the synchronous division of the parasite's daughter cells during endodyogeny, resulting in disordered rosettes. Moreover, the six conserved motifs of TgPP6C were required for efficient endodyogeny. Phosphoproteomic analysis revealed that ablation of TgPP6C predominately altered the phosphorylation status of proteins involved in the regulation of the parasite cell cycle. Deletion of TgPP6C significantly attenuated the parasite virulence in mice. Immunization of mice with TgPP6C-deficient type I RH strain induced protective immunity against challenge with a lethal dose of RH or PYS tachyzoites and Pru cysts. Taken together, the results show that TgPP6C contributes to the cell division, replication and pathogenicity in T. gondii.

DOI: https://doi.org/10.1371/journal.ppat.1011831
Nature. 2023 Dec 13.

In vitro production of cat-restricted Toxoplasma pre-sexual stages.

Ana Vera Antunes, Martina Shahinas, Christopher Swale, Dayana C Farhat, Chandra Ramakrishnan, Christophe Bruley, Dominique Cannella, Marie G Robert, Charlotte Corrao, Yohann Couté, Adrian B Hehl, Alexandre Bougdour, Isabelle Coppens, Mohamed-Ali Hakimi.

Sexual reproduction of Toxoplasma gondii, confined to the felid gut, remains largely uncharted owing to ethical concerns regarding the use of cats as model organisms. Chromatin modifiers dictate the developmental fate of the parasite during its multistage life cycle, but their targeting to stage-specific cistromes is poorly described1,2. Here we found that the transcription factors AP2XII-1 and AP2XI-2 operate during the tachyzoite stage, a hallmark of acute toxoplasmosis, to silence genes necessary for merozoites, a developmental stage critical for subsequent sexual commitment and transmission to the next host, including humans. Their conditional and simultaneous depletion leads to a marked change in the transcriptional program, promoting a full transition from tachyzoites to merozoites. These in vitro-cultured pre-gametes have unique protein markers and undergo typical asexual endopolygenic division cycles. In tachyzoites, AP2XII-1 and AP2XI-2 bind DNA as heterodimers at merozoite promoters and recruit MORC and HDAC3 (ref. 1), thereby limiting chromatin accessibility and transcription. Consequently, the commitment to merogony stems from a profound epigenetic rewiring orchestrated by AP2XII-1 and AP2XI-2. Successful production of merozoites in vitro paves the way for future studies on Toxoplasma sexual development without the need for cat infections and holds promise for the development of therapies to prevent parasite transmission.

DOI: https://doi.org/10.1038/s41586-023-06821-y
mBio. 2023 Dec 14. e0259523

Susceptibility of Toxoplasma gondii to autophagy in human cells relies on multiple interacting parasite loci.

Nicholas Rinkenberger, Alex Rosenberg, Joshua B Radke, Jaya Bhushan, Tadakimi Tomita, Louis M Weiss, L David Sibley.

   IMPORTANCE: Autophagy is a process used by cells to recycle organelles and macromolecules and to eliminate intracellular pathogens. Previous studies have shown that some stains of Toxoplasma gondii are resistant to autophagy-dependent growth restriction, while others are highly susceptible. Although it is known that autophagy-mediated control requires activation by interferon gamma, the basis for why parasite strains differ in their susceptibility is unknown. Our findings indicate that susceptibility involves at least five unlinked parasite genes on different chromosomes, including several secretory proteins targeted to the parasite-containing vacuole and exposed to the host cell cytosol. Our findings reveal that susceptibility to autophagy-mediated growth restriction relies on differential recognition of parasite proteins exposed at the host-pathogen interface, thus identifying a new mechanism for cell-autonomous control of intracellular pathogens.

Keywords:  dense granule proteins; genetic mapping; innate immunity; interferon; intracellular parasite; linkage analysis; parasitophorous vacuole; quantitative trait locus; secretory proteins

DOI:  https://doi.org/10.1128/mbio.02595-23
PLoS Pathog. 2023 Dec 11. 19(12): e1011867

Functional and biochemical characterisation of the Toxoplasma gondii succinate dehydrogenase complex.

Mariana F Silva, Kiera Douglas, Sofia Sandalli, Andrew E Maclean, Lilach Sheiner.

The mitochondrial electron transport chain (mETC) is a series of membrane embedded enzymatic complexes critical for energy conversion and mitochondrial metabolism. In commonly studied eukaryotes, including humans and animals, complex II, also known as succinate dehydrogenase (SDH), is an essential four-subunit enzyme that acts as an entry point to the mETC, by harvesting electrons from the TCA cycle. Apicomplexa are pathogenic parasites with significant impact on human and animal health. The phylum includes Toxoplasma gondii which can cause fatal infections in immunocompromised people. Most apicomplexans, including Toxoplasma, rely on their mETC for survival, yet SDH remains largely understudied. Previous studies pointed to a divergent apicomplexan SDH with nine subunits proposed for the Toxoplasma complex, compared to four in humans. While two of the nine are homologs of the well-studied SDHA and B, the other seven have no homologs in SDHs of other systems. Moreover, SDHC and D, that anchor SDH to the membrane and participate in substrate bindings, have no homologs in Apicomplexa. Here, we validated five of the seven proposed subunits as bona fide SDH components and demonstrated their importance for SDH assembly and activity. We further find that all five subunits are important for parasite growth, and that disruption of SDH impairs mitochondrial respiration and results in spontaneous initiation of differentiation into bradyzoites. Finally, we provide evidence that the five subunits are membrane bound, consistent with their potential role in membrane anchoring, and we demonstrate that a DY motif in one of them, SDH10, is essential for complex formation and function. Our study confirms the divergent composition of Toxoplasma SDH compared to human, and starts exploring the role of the lineage-specific subunits in SDH function, paving the way for future mechanistic studies.

DOI: https://doi.org/10.1371/journal.ppat.1011867
Parasitol Res. 2023 Dec 14. 123(1): 45

A candidate virulence factor of Eimeria tenella (EtROP30) predicted by virulence enhancement of transgenic Toxoplasma gondii.

Bingxiang Wang, Ningning Zhao, Lingyu Sun, Qianqian Tan, Qianqian Xiao, Junpeng Chen, Jinxuan Li, Xiao Zhang, Xiaomin Zhao.

  Difficulties of in vitro culture and genetic manipulation of Eimeria tenella have hindered the screening of virulence factors in this parasite. In this study, the E. tenella rhoptry protein 30 (EtROP30) was expressed in Toxoplasma gondii (RH∆Ku80-EtROP30), and its effect on the proliferation and virulence of parasites was investigated. The results revealed that the expression of EtROP30 had no impact on the invasion and egress processes. However, the RH∆Ku80-EtROP30 strain formed larger plaques compared to the RH∆Ku80, indicating that the EtROP30 expression promotes T. gondii proliferation. Furthermore, the RH∆Ku80-EtROP30 strain exhibited greater pathogenicity, resulting in earlier mortality and shorter overall survival time compared to RH∆Ku80. These results imply that EtROP30 expression facilitates parasite intracellular proliferation and virulence in mice, suggesting that EtROP30 might be a candidate virulence factor of E. tenella.

Keywords:  Eimeria tenella; Proliferation; Rhoptry protein; Virulence factor

DOI:  https://doi.org/10.1007/s00436-023-08079-9
Parasitol Res. 2023 Dec 13. 123(1): 34

Toxoplasma gondii-induced neutrophil extracellular traps are relevant to glycolysis, TLR2, and TLR4 MAPK signaling pathway in goats.

Zha Jin, Qinqin Jin, Meiyi Chen, Wei Liu, Hongrong Hong, Yuqian Jiang, Xinxin Gao, Yuxiao Qian, Zedong Wang, Quan Liu, Zhengkai Wei.

  Toxoplasma gondii (T. gondii) exhibits a significantly high prevalence of infection in goats, leading to adverse consequences such as abortion and stillbirth in ewes, thereby posing a substantial challenge to the goat farming industry. Neutrophil extracellular traps (NETs) have been shown to capture T. gondii in goats; however, the precise mechanisms underlying NET release in goats remain poorly understood. Therefore, the aim of our research was to elucidate the involved mechanism. We assessed the cytotoxicity of T. gondii on neutrophils using CCK-8 assay, visualized the structure of T. gondii-induced goat NETs through immunofluorescence, quantified ROS release during T. gondii-induced NET formation using fluorescence microplate analysis, and employed inhibitors targeting TLR 2, TLR4, NADPH oxidase, ERK1/2, and P38 MAPK signaling pathways as well as glycolysis to dissect the mechanisms underlying T. gondii-induced NET release. Within 1 h, T. gondii did not exhibit significant cytotoxicity towards neutrophils in our findings. The formation of typical NET structures induced by T. gondii involved DNA, citrullinated histone 3 (citH3), and neutrophil elastase (NE). Additionally, T. gondii significantly stimulated the release of NETs in goats. The process was accompanied by the production of reactive oxygen species (ROS) mediated through NADPH oxidase, p38, and ERK1/2 signaling pathways. Inhibition of these pathways resulted in a decrease in NET release. Moreover, inhibition of TLR 2, TLR4, and glycolysis also led to a reduction in T. gondii-induced NET release. Overall, our study demonstrates that T. gondii can induce characteristic NET structures and elucidates the involvement of various mechanisms including TLR2/TLR4 signaling pathway activation, NADPH oxidase activity modulation via ROS production regulation through p38 MAPK and ERK1/2 signaling pathways, and glycolysis regulation during the innate immune response against T. gondii infection in goats.

Keywords:  Goats; Neutrophil; Neutrophil extracellular traps; Toxoplasma gondii

DOI:  https://doi.org/10.1007/s00436-023-08041-9
Microbiome. 2023 Dec 12. 11(1): 273

Gut microbiota-related metabolite alpha-linolenic acid mitigates intestinal inflammation induced by oral infection with Toxoplasma gondii.

Jing Yang, Songhao Liu, Qian Zhao, Xiaobing Li, Kangfeng Jiang.

   BACKGROUND: Oral infection with cysts is the main transmission route of Toxoplasma gondii (T. gondii), which leads to lethal intestinal inflammation. It has been widely recognized that T. gondii infection alters the composition and metabolism of the gut microbiota, thereby affecting the progression of toxoplasmosis. However, the potential mechanisms remain unclear. In our previous study, there was a decrease in the severity of toxoplasmosis after T. gondii α-amylase (α-AMY) was knocked out. Here, we established mouse models of ME49 and Δα-amy cyst infection and then took advantage of 16S rRNA gene sequencing and metabolomics analysis to identify specific gut microbiota-related metabolites that mitigate T. gondii-induced intestinal inflammation and analyzed the underlying mechanism.
RESULTS: There were significant differences in the intestinal inflammation between ME49 cyst- and Δα-amy cyst-infected mice, and transferring feces from mice infected with Δα-amy cysts into antibiotic-treated mice mitigated colitis caused by T. gondii infection. 16S rRNA gene sequencing showed that the relative abundances of gut bacteria, such as Lactobacillus and Bacteroides, Bifidobacterium, [Prevotella], Paraprevotella and Macellibacteroides, were enriched in mice challenged with Δα-amy cysts. Spearman correlation analysis between gut microbiota and metabolites indicated that some fatty acids, including azelaic acid, suberic acid, alpha-linolenic acid (ALA), and citramalic acid, were highly positively correlated with the identified bacterial genera. Both oral administration of ALA and fecal microbiota transplantation (FMT) decreased the expression of pro-inflammatory cytokines and restrained the MyD88/NF-κB pathway, which mitigated colitis and ultimately improved host survival. Furthermore, transferring feces from mice treated with ALA reshaped the colonization of beneficial bacteria, such as Enterobacteriaceae, Proteobacteria, Shigella, Lactobacillus, and Enterococcus.
CONCLUSIONS: The present findings demonstrate that the host gut microbiota is closely associated with the severity of T. gondii infection. We provide the first evidence that ALA can alleviate T. gondii-induced colitis by improving the dysregulation of the host gut microbiota and suppressing the production of pro-inflammatory cytokines via the MyD88/NF-κB pathway. Our study provides new insight into the medical application of ALA for the treatment of lethal intestinal inflammation caused by Toxoplasma infection. Video Abstract.

Keywords:  Alpha-linolenic acid; Fecal microbiota transplantation; Gut microbiota; Intestinal inflammation; Metabolite; Toxoplasma gondii

DOI:  https://doi.org/10.1186/s40168-023-01681-0
Chembiochem. 2023 Dec 11. e202300596

Histone globular domain epigenetic modifications: The regulators of chromatin dynamics in malaria parasite.

C A Jabeena, Arumugam Rajavelu.

  Plasmodium species adapt a complex lifecycle with multiple phenotypes to survive inside various cell types of humans and mosquitoes. Stage-specific gene expression in the developmental stages of parasites is tightly controlled in Plasmodium species; however, the underlying mechanisms have yet to be explored. Genome organization and gene expression for each stage of the malaria parasite need to be better characterized. Recent studies indicated that epigenetic modifications of histone proteins play a vital role in chromatin plasticity. Like other eukaryotes, Plasmodium species N-terminal tail modifications form a distinct "histone code," which creates the docking sites for histone reader proteins, including gene activator/repressor complexes, to regulate gene expression. The emerging research findings shed light on various unconventional epigenetic changes in histone proteins' core/globular domain regions, which might contribute to the chromatin organization in different developmental stages of the malaria parasite. The malaria parasite lost many transcription factors during evolution, and it is proposed that the nature of local chromatin structure essentially regulates the stage-specific gene expression. This review highlights recent discoveries of unconventional histone globular domain epigenetic modifications and their functions in regulating chromatin structure dynamics in various developmental stages of malaria parasites.

Keywords:  Chromatin, Gene regulation, Histone epigenetics, Malaria parasite, Plasmodium

DOI:  https://doi.org/10.1002/cbic.202300596
Nature. 2023 Dec 13.

Cat parasite Toxoplasma tricked to grow in a dish.

Nick Petrić Howe, Shamini Bundell.



Keywords:  Chemistry; Diseases; Parasitology; Technology

DOI:  https://doi.org/10.1038/d41586-023-04016-z
Acta Vet Scand. 2023 Dec 12. 65(1): 53

Toxoplasma gondii seroprevalence in reindeer (Rangifer tarandus tarandus L.) in northern Sweden: a cross-sectional study from 2014.

Arja Helena Kautto, Abbey Olsen, Camilla Wallander, Ivar Vågsholm.

   BACKGROUND: Toxoplasma gondii is a parasitic protozoan that can infect a wide range of warm-blooded animals, including humans. The infection with T. gondii, is of particular concern due to its potential impact on human and animal health. In Sweden, semi-domesticated reindeer (Rangifer tarandus tarandus L.) is an important species both economically and culturally, but susceptibility to Toxoplasma infection and seroprevalence in reindeer herds remain relatively understudied.
RESULTS: A total of 528 reindeer, sampled at two slaughterhouses in Sweden in 2014, were investigated for antibodies to T. gondii. Specific antibodies to T. gondii were found in 5 of 209 (2.3%) tested adult reindeer and in 6 of 308 (1.9%) tested calves, giving an apparent total prevalence of 2.1% (95% confidence interval 1.1-3.8%). None of four putative risk factors studied (sex, age, type of grazing area, county) were statistically associated with T. gondii seroprevalence.
CONCLUSIONS: Swedish semi-domesticated reindeer are exposed to T. gondii and may harbour infectious tissue cysts. To mitigate the risk of T. gondii infection in consumers, reindeer meat should be frozen or cooked thoroughly before consumption. The global climate change may influence the seroprevalence and possible associated risk factors for T. gondii in reindeer. To be able to manage the risk and get better advice to the consumers there is a need for further investigations covering the whole spectra of herding conditions for reindeer.

Keywords:  Cervid; ELISA; Farmed game; Food safety; Meat safety; Toxoplasmosis; Zoonosis

DOI:  https://doi.org/10.1186/s13028-023-00717-7
Parasit Vectors. 2023 Dec 13. 16(1): 454

Lentinan has a beneficial effect on cognitive deficits induced by chronic Toxoplasma gondii infection in mice.

Shuxi Liu, Ziyi Yan, Yuan Peng, Yunqiu Liu, Yiling Li, Daxiang Xu, Yuying Gong, Zeyu Cui, Yongshui Wu, Yumei Zhang, Dahui Wang, Wei Pan, Xiaoying Yang.

   BACKGROUND: Toxoplasma gondii (T. gondii) is increasingly considered a risk factor for neurodegenerative diseases. However, there is only limited information on the development of drugs for T. gondii infection. Lentinan from Lentinula edodes is a bioactive ingredient with the potential to enhance anti-infective immunity. The present study aimed to investigate the neuroprotective effect of lentinan on T. gondii-associated cognitive deficits in mice.
METHODS: A chronic T. gondii infection mouse model was established by administering 10 cysts of T. gondii by gavage. Lentinan was intraperitoneally administered 2 weeks before infection. Behavioral tests, RNA sequencing, immunofluorescence, transmission electron microscopy and Golgi-Cox staining were performed to assess the effect of lentinan on cognitive deficits and neuropathology in vivo. In vitro, the direct and indirect effects of lentinan on the proliferation of T. gondii tachyzoites were evaluated in the absence and presence of BV-2 cells, respectively.
RESULTS: Lentinan prevented T. gondii-induced cognitive deficits and altered the transcriptome profile of genes related to neuroinflammation, microglial activation, synaptic function, neural development and cognitive behavior in the hippocampus of infected mice. Moreover, lentinan reduced the infection-induced accumulation of microglia and downregulated the mRNA expression of proinflammatory cytokines. In addition, the neurite and synaptic ultrastructural damage in the hippocampal CA1 region due to infection was ameliorated by lentinan administration. Lentinan decreased the cyst burden in the brains of infected mice, which was correlated with behavioral performance. In line with this finding, lentinan could significantly inhibit the proliferation of T. gondii tachyzoites in the microglial cell line BV2, although lentinan had no direct inhibitory effect on parasite growth.
CONCLUSIONS: Lentinan prevents cognitive deficits via the improvement of neurite impairment and synaptic loss induced by T. gondii infection, which may be associated with decreased cyst burden in the brain. Overall, our findings indicate that lentinan can ameliorate T. gondii-related neurodegenerative diseases.

Keywords:  Cognitive deficits; Hippocampus; Lentinan; Neuroinflammation; Toxoplasma gondii

DOI:  https://doi.org/10.1186/s13071-023-06023-5
Front Cell Infect Microbiol. 2023 ;13 997245

The patatin-like phospholipase PfPNPLA2 is involved in the mitochondrial degradation of phosphatidylglycerol during Plasmodium falciparum blood stage development.

Serena Shunmugam, Nyamekye Quansah, Ansgar Flammersfeld, Md Muzahidul Islam, Juliane Sassmannshausen, Sandra Bennink, Yoshiki Yamaryo-Botté, Gabriele Pradel, Cyrille Y Botté.

  Plasmodium falciparum is an Apicomplexa responsible for human malaria, a major disease causing more than ½ million deaths every year, against which there is no fully efficient vaccine. The current rapid emergence of drug resistances emphasizes the need to identify novel drug targets. Increasing evidences show that lipid synthesis and trafficking are essential for parasite survival and pathogenesis, and that these pathways represent potential points of attack. Large amounts of phospholipids are needed for the generation of membrane compartments for newly divided parasites in the host cell. Parasite membrane homeostasis is achieved by an essential combination of parasite de novo lipid synthesis/recycling and massive host lipid scavenging. Latest data suggest that the mobilization and channeling of lipid resources is key for asexual parasite survival within the host red blood cell, but the molecular actors allowing lipid acquisition are poorly characterized. Enzymes remodeling lipids such as phospholipases are likely involved in these mechanisms. P. falciparum possesses an unusually large set of phospholipases, whose functions are largely unknown. Here we focused on the putative patatin-like phospholipase PfPNPLA2, for which we generated an glmS-inducible knockdown line and investigated its role during blood stages malaria. Disruption of the mitochondrial PfPNPLA2 in the asexual blood stages affected mitochondrial morphology and further induced a significant defect in parasite replication and survival, in particular under low host lipid availability. Lipidomic analyses revealed that PfPNPLA2 specifically degrades the parasite membrane lipid phosphatidylglycerol to generate lysobisphosphatidic acid. PfPNPLA2 knockdown further resulted in an increased host lipid scavenging accumulating in the form of storage lipids and free fatty acids. These results suggest that PfPNPLA2 is involved in the recycling of parasite phosphatidylglycerol to sustain optimal intraerythrocytic development when the host resources are scarce. This work strengthens our understanding of the complex lipid homeostasis pathways to acquire lipids and allow asexual parasite survival.

Keywords:  Apicomplexa; lipid; lipidomic; malaria; metabolism; mitochondria; phospholipase

DOI:  https://doi.org/10.3389/fcimb.2023.997245
Int J Mol Sci. 2023 Dec 02. pii: 17072. [Epub ahead of print]24(23):

HDAC1: An Essential and Conserved Member of the Diverse Zn2+-Dependent HDAC Family Driven by Divergent Selection Pressure.

Jing-Fang Yang, Le-Rong Shi, Ke-Chen Wang, Li-Long Huang, Yun-Shuang Deng, Mo-Xian Chen, Fang-Hao Wan, Zhong-Shi Zhou.

  Zn2+-dependent histone deacetylases (HDACs) are enzymes that regulate gene expression by removing acetyl groups from histone proteins. These enzymes are essential in all living systems, playing key roles in cancer treatment and as potential pesticide targets. Previous phylogenetic analyses of HDAC in certain species have been published. However, their classification and evolutionary origins across biological kingdoms remain unclear, which limits our understanding of them. In this study, we collected the HDAC sequences from 1451 organisms and performed analyses. The HDACs are found to diverge into three classes and seven subclasses under divergent selection pressure. Most subclasses show species specificity, indicating that HDACs have evolved with high plasticity and diversification to adapt to different environmental conditions in different species. In contrast, HDAC1 and HDAC3, belonging to the oldest class, are conserved and crucial in major kingdoms of life, especially HDAC1. These findings lay the groundwork for the future application of HDACs.

Keywords:  HDAC1; Zn2+-dependent histone deacetylases; divergent selection pressures; evolutionary plasticity; phylogenetic analysis

DOI:  https://doi.org/10.3390/ijms242317072
J Med Chem. 2023 Dec 07.

Discovery of YSR734: A Covalent HDAC Inhibitor with Cellular Activity in Acute Myeloid Leukemia and Duchenne Muscular Dystrophy.

Yasir S Raouf, Abootaleb Sedighi, Mulu Geletu, Geordon A Frere, Rebecca G Allan, Nabanita Nawar, Elvin D de Araujo, Patrick T Gunning.

Histone deacetylases (HDACs) have emerged as powerful epigenetic modifiers of histone/non-histone proteins via catalyzing the deacetylation of ε-N-acetyl lysines. The dysregulated activity of these Zn2+-dependent hydrolases has been broadly implicated in disease, notably cancer. Clinically, the recurring dose-limiting toxicities of first-generation HDACi sparked a paradigm shift toward safer isoform-specific molecules. With pervasive roles in aggressive diseases, there remains a need for novel approaches to target these enzymes. Herein, we report the discovery of YSR734, a first-in-class covalent HDACi, with a 2-aminobenzanilide Zn2+ chelate and a pentafluorobenzenesulfonamide electrophile. This class I selective proof of concept modified HDAC2Cys274 (catalytic domain), with nM potency against HDAC1-3, sub-μM activity in MV4-11 cells, and limited cytotoxicity in MRC-9 fibroblasts. In C2C12 myoblasts, YSR734 activated muscle-specific biomarkers myogenin/Cav3, causing potent differentiation into myotubes (applications in Duchenne Muscular Dystrophy). Current efforts are focused on improving in vivo ADME toward a preclinical covalent HDACi.

DOI: https://doi.org/10.1021/acs.jmedchem.3c01236
Mol Cell Biochem. 2023 Dec 08.

The dark side of SIRT7.

Francisco Alejandro Lagunas-Rangel.

  Sirtuin 7 (SIRT7) is a member of the sirtuin family and has emerged as a key player in numerous cellular processes. It exhibits various enzymatic activities and is predominantly localized in the nucleolus, playing a role in ribosomal RNA expression, DNA damage repair, stress response and chromatin compaction. Recent studies have revealed its involvement in diseases such as cancer, cardiovascular and bone diseases, and obesity. In cancer, SIRT7 has been found to be overexpressed in multiple types of cancer, including breast cancer, clear cell renal cell carcinoma, lung adenocarcinoma, prostate adenocarcinoma, hepatocellular carcinoma, and gastric cancer, among others. In general, cancer cells exploit SIRT7 to enhance cell growth and metabolism through ribosome biogenesis, adapt to stress conditions and exert epigenetic control over cancer-related genes. The aim of this review is to provide an in-depth understanding of the role of SIRT7 in cancer carcinogenesis, evolution and progression by elucidating the underlying molecular mechanisms. Emphasis is placed on unveiling the intricate molecular pathways through which SIRT7 exerts its effects on cancer cells. In addition, this review discusses the feasibility and challenges associated with the development of drugs that can modulate SIRT7 activity.

Keywords:  Acetylation; DNA repair; Epigenetic regulation; Ribosome biogenesis; SIRT7 inhibitors

DOI:  https://doi.org/10.1007/s11010-023-04869-y
Epigenetics Chromatin. 2023 Dec 14. 16(1): 49

O-GlcNAcylation: the sweet side of epigenetics.

Thomas Dupas, Benjamin Lauzier, Serge McGraw.

  Histones display a wide variety of post-translational modifications, including acetylation, methylation, and phosphorylation. These epigenetic modifications can influence chromatin structure and function without altering the DNA sequence. Histones can also undergo post-translational O-GlcNAcylation, a rather understudied modification that plays critical roles in almost all biological processes and is added and removed by O-linked N-acetylglucosamine transferase and O-GlcNAcase, respectively. This review provides a current overview of our knowledge of how O-GlcNAcylation impacts the histone code both directly and by regulating other chromatin modifying enzymes. This highlights the pivotal emerging role of O-GlcNAcylation as an essential epigenetic marker.

Keywords:  Epigenetics; Histone modification; O-GlcNAcylation

DOI:  https://doi.org/10.1186/s13072-023-00523-5
Chimia (Aarau). 2022 May 25. 76(5): 448-453

Current HDAC Inhibitors in Clinical Trials.

Elisabetta Di Bello, Beatrice Noce, Rossella Fioravanti, Antonello Mai.

  Epigenetic modifications in eukaryotic biological pathways can lead to the up- or downregulation of regulatory proteins contributing to disease onset and progression. In the last three decades, histone deacetylases (HDACs) are among the most studied epigenetic targets. In fact, aberrant HDAC expression is associated with numerous types of cancer and neurodegenerative disorders, making HDACs promising molecular targets for the design of new drugs. Many HDAC inhibitors (HDACi) are currently in clinical evaluation for various types of cancer, and some of them reached the market after approval by the Food and Drug Administration (FDA). The present review summarizes the various HDAC classes and relative isoforms. Then we discuss different class or isoform-selective HDACi with a strong emphasis on late-stage preclinical candidates and drugs in clinical studies. Last but not least, we shed light on the pharmacokinetic challenges and future directions in HDACi design.

Keywords:  Cancer; Clinical studies; Epigenetics; Histone deacetylases

DOI:  https://doi.org/10.2533/chimia.2022.448