bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2024–11–24
ten papers selected by
Lakesh Kumar, BITS Pilani
  1. The apicoplast biogenesis and metabolism: current progress and questions.
  2. Functional dissection of prenyltransferases reveals roles in endocytosis and secretory vacuolar sorting in type 2-ME49 strain of toxoplasma gondii.
  3. The (patho)physiological roles of the individual deacylase activities of a sirtuin.
  4. A narrative review of the histone acetylation and deacetylation during mammalian spermatogenesis.
  5. Dense granule protein 41 of Neospora caninum modulates tachyzoite egress by regulating microneme secretion.
  6. Targeting lysine acetylation readers and writers.
  7. Eimeria: Navigating complex intestinal ecosystems.
  8. The Enigmatic Role of SIRT2 in the Cardiovascular System: Deciphering its Protective and Detrimental Actions to Unlock New Avenues for Therapeutic Intervention.
  9. An NAD+ with Dually Modified Adenine for Labeling ADP-Ribosylation-Specific Proteins.
  10. ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion.
  1. Trends Parasitol. 2024 Nov 19. pii: S1471-4922(24)00308-8. [Epub ahead of print]
    The apicoplast biogenesis and metabolism: current progress and questions.
    Xiaowei Chen, Xun Suo, Guan Zhu, Bang Shen.
      Many apicomplexan parasites have a chloroplast-derived apicoplast containing several metabolic pathways. Recent studies have greatly expanded our understanding of apicoplast biogenesis and metabolism while also raising new questions. Here, we review recent progress on the biological roles of individual metabolic pathways, focusing on two medically important parasites, Plasmodium spp. and Toxoplasma gondii. We highlight the similarities and differences in how similar apicoplast metabolic pathways are utilized to adapt to different parasitic lifestyles. The execution of apicoplast metabolic functions requires extensive interactions with other subcellular compartments, but the underlying mechanisms remain largely unknown. Apicoplast metabolic functions have historically been considered attractive drug targets, and a comprehensive understanding of their metabolic capacities and interactions with other organelles is essential to fully realize their potential.
    Keywords:  Plasmodium spp.; Toxoplasma gondii; apicoplast metabolism; endosymbiosis; organelle biogenesis; secondary plastid
    DOI:  https://doi.org/10.1016/j.pt.2024.10.019
  2. Virulence. 2024 Nov 21. 2432681
    Functional dissection of prenyltransferases reveals roles in endocytosis and secretory vacuolar sorting in type 2-ME49 strain of toxoplasma gondii.
    Qiangqiang Wang, Yuanfeng Wang, Jinghui Wang, Wenjie Tian, Naiwen Zhang, Shaojun Long, Shuai Wang.
      Prenyltransferases act essential roles in the prenylation modification, which is significant for proteins, like small GTPases to execute various important activities in Toxoplasma gondii (T.gondii). The structures and partial functions of prenyltransferases (FTase, GGTase-I, and GGTase-II) in prenylation process have been dissected in T. gondii. However, the cellular effects of prenyltransferases on type 2-ME49 strain of Toxoplasma are largely unknown. To address this gap, CRISPR/Cas9-based gene-editing technology was employed to construct conditional knockdown strains of prenyltransferases in ME49 strain. Subsequent observation of ingestion ability of host cytosolic molecules (e.g, green fluorescent protein [GFP]) and status of secretory vacuolar sorting post-knockdown of prenyltransferases revealed significant findings. Our study demonstrated that degradation of FTase and GGTase-II notably affected the trafficking of endocytic GFP and vacuolar secretory trafficking to rhoptry bulb. Additionally, depletion of GGTase-II led to disordered endoplasmic reticulum and microtubules, as well as impaired gliding motility. The integrity of mitochondrion was damaged after degradation of GGTase-I. These findings underscore the critical functions of prenyltransferases in endocytosis and secretory vacuolar sorting in ME49 strain of T. gondii, thereby enhancing our understanding of prenyltransferases as potential drug targets.
    Keywords:  ME49; Protein prenylation; endocytosis; prenyltransferases; secretory vacuolar sorting; toxoplasma gondii
    DOI:  https://doi.org/10.1080/21505594.2024.2432681
  3. Chem Biol Drug Des. 2024 Feb;103(2): e14460
    The (patho)physiological roles of the individual deacylase activities of a sirtuin.
    Weiping Zheng.
      Since the discovery of the sirtuin family founding member (i.e., the yeast silent information regulator 2 (sir2) protein) in 2000, more and more sirtuin proteins have been identified and are currently known to be present in organisms from all the three kingdoms of life (i.e., bacteria, archaea, and eukarya). Seven sirtuin proteins have been identified in mammals including humans, that is, SIRT1/2/3/4/5/6/7. Sirtuin proteins are a class of enzymes with primary catalytic activity being the β-nicotinamide adenine dinucleotide (β-NAD+ or NAD+)-dependent deacylation from the Nε-acyl-lysine residues on cellular proteins. Many sirtuins (e.g., human SIRT1/2/3/4/5/6/7) have been found to each possess multiple individual deacylase activities acting on Nε-acyl-lysine substrates with different acyl groups ranging from the simple formyl and acetyl to the more complex groups like succinyl and myristoyl; however, our current knowledge on the (patho)physiological roles of these individual deacylase activities is still limited, which could be due to the currently still thin research toolbox for investigation (i.e., the deacylase-selective sirtuin mutant and inhibitor/activator). In this article, an updated account on the subject matter will be presented with biochemical and medicinal chemistry perspectives.
    Keywords:  (patho)physiological role; Nε‐acyl‐lysine; deacylase; deacylation; medicinal chemistry; sirtuin
    DOI:  https://doi.org/10.1111/cbdd.14460
  4. Biochimie. 2024 Nov 18. pii: S0300-9084(24)00266-9. [Epub ahead of print]
    A narrative review of the histone acetylation and deacetylation during mammalian spermatogenesis.
    Tuba Kablan, Efe Biyikli, Nazlican Bozdemir, Fatma Uysal.
      Dynamic epigenetic control is essential for proper spermatogenesis. Spermatogenesis is a unique mechanism that includes recombination, meiosis, and the conversion of histones to protamines. Epigenetics refers to the ability to modify gene expression without affecting DNA strands directly and helps to regulate the dynamic gene expression throughout the differentiation process of spermatogonium stem cells. Histone alterations and DNA methylation control the epigenome. While histone modifications can result in either expression or repression depending on the type of modification, the type of histone protein, and its specific residue, histone acetylation is one of the changes that typically results in gene expression. Histone acetyltransferases (HATs) add an acetyl group to the amino-terminal of the core histone proteins, causing histone acetylation. On the other hand, histone deacetylases (HDACs) catalyze histone deacetylation, which is linked to the suppression of gene expression. This review highlights the significance of HATs and HDACs during mammalian spermatogenesis and focuses on what is known about changes in their expression.
    Keywords:  HATs; HDACs; acetylation; epigenetics; spermatogenesis
    DOI:  https://doi.org/10.1016/j.biochi.2024.11.011
  5. Parasitol Res. 2024 Nov 18. 123(11): 386
    Dense granule protein 41 of Neospora caninum modulates tachyzoite egress by regulating microneme secretion.
    Jing Yang, Yanqun Pei, Xianmei Wang, Zhu Ying, Zifu Zhu, Qun Liu, Jing Liu.
      Egress represents a crucial process employed by Neospora caninum in the establishment of infection. Dense granule proteins (GRAs), secreted by the dense granule, play significant roles in modifying the parasitophorous vacuole, maintenance of morphology, and regulating host-cell interactions. However, their precise involvement in tachyzoite egress remains inadequately characterized. In this study, we identified a homologous gene, Ncgra41, corresponding to the dense granule protein 41 (GRA41) of Toxoplasma gondii, which is associated with egress, utilizing NCBI and ToxoDB databases. NcGRA41 is localized extracellularly within dense granules and intracellularly within parasitic vacuoles. Deletion of NcGRA41 did not affect tachyzoites invasion or proliferation but significantly reduced egress capacity and pathogenicity in mice. The phenotypic characteristics were restored in a complementary strain. Further investigation revealed that the absence of NcGRA41 reduced gliding motility and the transcription level of the subtilisin-like protein (SUB1). A microneme secretion assay demonstrated a significant decrease in NcMIC1 secretion, along with reduced expression levels of NcMIC1, NcMIC4, and NcMIC8. These findings demonstrate that NcGRA41, a novel dense granule protein in N. caninum, modulates tachyzoites egress and influences pathogenicity by regulating microneme secretion.
    Keywords:   Neospora caninum ; Dense granule protein 41; Egress; Microneme secretion; Pathogenicity
    DOI:  https://doi.org/10.1007/s00436-024-08405-9
  6. Nat Rev Drug Discov. 2024 Nov 21.
    Targeting lysine acetylation readers and writers.
    Ming-Ming Zhou, Philip A Cole.
      Lysine acetylation is a major post-translational modification in histones and other proteins that is catalysed by the 'writer' lysine acetyltransferases (KATs) and mediates interactions with bromodomains (BrDs) and other 'reader' proteins. KATs and BrDs play key roles in regulating gene expression, cell growth, chromatin structure, and epigenetics and are often dysregulated in disease states, including cancer. There have been accelerating efforts to identify potent and selective small molecules that can target individual KATs and BrDs with the goal of developing new therapeutics, and some of these agents are in clinical trials. Here, we summarize the different families of KATs and BrDs, discuss their functions and structures, and highlight key advances in the design and development of chemical agents that show promise in blocking the action of these chromatin proteins for disease treatment.
    DOI:  https://doi.org/10.1038/s41573-024-01080-6
  7. PLoS Pathog. 2024 Nov;20(11): e1012689
    Eimeria: Navigating complex intestinal ecosystems.
    Shengjie Weng, Erjie Tian, Meng Gao, Siyu Zhang, Guodong Yang, Bianhua Zhou.
      Eimeria is an intracellular obligate apicomplexan parasite that parasitizes the intestinal epithelial cells of livestock and poultry, exhibiting strong host and tissue tropism. Parasite-host interactions involve complex networks and vary as the parasites develop in the host. However, understanding the underlying mechanisms remains a challenge. Acknowledging the lack of studies on Eimeria invasion mechanism, we described the possible invasion process through comparative analysis with other apicomplexan parasites and explored the fact that parasite-host interactions serve as a prerequisite for successful recognition, penetration of the intestinal mechanical barrier, and completion of the invasion. Although it is recognized that microbiota can enhance the host immune capacity to resist Eimeria invasion, changes in the microenvironment can, in turn, contribute to Eimeria invasion and may be associated with reduced immune capacity. We also discuss the immune evasion strategies of Eimeria, emphasizing that the host employs sophisticated immune regulatory mechanisms to suppress immune evasion by parasites, thereby sustaining a balanced immune response. This review aims to deepen our understanding of Eimeria-host interactions, providing a theoretical basis for the study of the pathogenicity of Eimeria and the development of novel anticoccidial drugs.
    DOI:  https://doi.org/10.1371/journal.ppat.1012689
  8. Curr Probl Cardiol. 2024 Nov 18. pii: S0146-2806(24)00564-4. [Epub ahead of print] 102929
    The Enigmatic Role of SIRT2 in the Cardiovascular System: Deciphering its Protective and Detrimental Actions to Unlock New Avenues for Therapeutic Intervention.
    Abdulaziz Hassan Alhasaniah, Mohammed Alissa, Fahmy Gad Elsaid, Mahdi H Alsugoor, Mohammed S AlQahtani, Anwer Alessa, Khalid Jambi, Ghadah Shukri Albakri, Elizabeth Bennett.
      Cardiovascular diseases (CVDs) are leading causes of mortality throughout the world, and hence, there is a critical need to elucidate their molecular mechanisms. The Sirtuin (SIRT) family of NAD+-dependent enzymes has recently been shown to play a critical role in cardiovascular health and disease, and several SIRT isoforms, especially SIRT1 and SIRT3, have been amply investigated. However, the precise function of SIRT2 is only partially explored. Here, we review the current understanding of the involvement of SIRT2 in various cardiovascular pathologies, such as cardiac hypertrophy, ischemia-reperfusion injury, diabetic cardiomyopathy, and vascular dysfunction, with emphasis placed on the context-dependent protective or deleterious actions of SIRT2, including its wide array of catalytic activities which span beyond deacetylation. Furthermore, the review uncovers several unresolved research gaps for SIRT2 mechanisms by which SIRT2 modulates cardiac and vascular function during development and aging, thereby paving the way for the discovery of novel therapeutic targets as well as SIRT2-targeted interventions in the prevention and treatment of various cardiovascular diseases.
    Keywords:  Atherosclerosis; Cardiovascular diseases; Heart failure; Myocardial infarction; Myocardial ischemia-reperfusion injury; diabetic cardiomyopathy
    DOI:  https://doi.org/10.1016/j.cpcardiol.2024.102929
  9. Tetrahedron. 2024 Dec 01. pii: 134361. [Epub ahead of print]168
    An NAD+ with Dually Modified Adenine for Labeling ADP-Ribosylation-Specific Proteins.
    Lei Zhang, Xiao-Nan Zhang, Arshad J Ansari, Yong Zhang.
      Protein adenosine diphosphate (ADP)-ribosylation participates in various pivotal cellular events. Its readers and erasers play key roles in modulating ADP-ribosylation-based signaling pathways. Unambiguous assignments of readers and erasers to individual ADP-ribosylated proteins provide insightful knowledge on ADP-ribosylation biology and require the development of tools and technologies for this goal. Herein, we report the design and the synthesis of a nicotinamide adenine dinucleotide (NAD+) carrying a photoactive and a clickable group. Functioning as a substrate for poly-ADP-ribosylation (PARylation), this NAD+ mimic with dually modified adenine enables covalent crosslinking and labeling of proteins bound to PARylation, representing a new photoaffinity probe for studying this critical post-translational modification.
    Keywords:  ADP-ribosylation; NAD+; PARP1; photoaffinity probe
    DOI:  https://doi.org/10.1016/j.tet.2024.134361
  10. Cell Metab. 2024 Nov 12. pii: S1550-4131(24)00411-X. [Epub ahead of print]
    ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion.
    Rongxuan Zhu, Xianglai Ye, Xiaotong Lu, Liwei Xiao, Ming Yuan, Hong Zhao, Dong Guo, Ying Meng, Hongkuan Han, Shudi Luo, Qingang Wu, Xiaoming Jiang, Jun Xu, Zhonghui Tang, Yizhi Jane Tao, Zhimin Lu.
      Lactyl-coenzyme A (CoA)-dependent histone lysine lactylation impacts gene expression and plays fundamental roles in biological processes. However, mammalian lactyl-CoA synthetases and their regulation of histone lactylation have not yet been identified. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces extracellular signal-regulated kinase (ERK)-mediated S267 phosphorylation of acetyl-CoA synthetase 2 (ACSS2) and its subsequent nuclear translocation and complex formation with lysine acetyltransferase 2A (KAT2A). Importantly, ACSS2 functions as a bona fide lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. Consequently, KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. A combination treatment with an ACSS2-KAT2A interaction-blocking peptide and an anti-PD-1 antibody induces an additive tumor-inhibitory effect. These findings uncover ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development.
    Keywords:  ACSS2; KAT2A; PD-L1; histone lactylation; lactate
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.015
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