bims-toxgon 2024-06-16 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2024–06–16
28 papers selected by
Lakesh Kumar, BITS Pilani

Rhoptry proteins affect the placental barrier in the context of Toxoplasma gondii infection: Signaling pathways and functions.
Differential transcriptome study on the damage of testicular tissues caused by chronic infection of T. gondii in mice.
The Toxoplasma oxygen-sensing protein, TgPhyA, is required for resistance to interferon gamma-mediated nutritional immunity in mice.
Evaluating the Risk Landscape of Hawaiian Monk Seal Exposure to Toxoplasma gondii.
Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis.
Coenzyme A biosynthesis: mechanisms of regulation, function and disease.
Harnessing cholesterol uptake of malaria parasites for therapeutic applications.
Phosphorylation of mammalian cytosolic and mitochondrial malate dehydrogenase: insights into regulation.
Advances in SIRT3 involvement in regulating autophagy-related mechanisms.
Citrate synthase variants improve yield of acetyl-CoA derived 3-hydroxybutyrate in Escherichia coli.
HDAC3 inhibitors: a patent review of their broad-spectrum applications as therapeutic agents.
Active E. coli heteromeric acetyl-CoA carboxylase forms polymorphic helical tubular filaments.
Sirtuin E deacetylase is required for full virulence of Aspergillus fumigatus.
Plasmodium LCCL domain-containing modular proteins have their origins in the ancestral alveolate.
Insight in Quinazoline-based HDAC Inhibitors as Anti-cancer Agents.
Malate dehydrogenase (MDH) in cancer: a promiscuous enzyme, a redox regulator, and a metabolic co-conspirator.
A systematic review of epigenetic interplay in kidney diseases: Crosstalk between long noncoding RNAs and methylation, acetylation of chromatin and histone.
Emerging role of HDAC11 in skeletal muscle biology.
The critical roles of three sugar-related proteins (HXK, SnRK1, TOR) in regulating plant growth and stress responses.
Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues.
Substrate and Functional Diversity of Protein Lysine Post-translational Modifications.
SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF.
Epigenetically Rewiring Metabolic Genes via SIRT6 Orchestrates MSC Fate Determination.
Epigenetic control of gene expression by cellular metabolisms in plants.
Metabolic Signaling in Cancer.
SOD3 suppresses early cellular immune responses to parasite infection.
Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription.
Zinc(II) Complexes of SIRTi1/2 Analogues Transmetallating with Copper Ions and Inducing ROS Mediated Paraptosis.

Ecotoxicol Environ Saf. 2024 Jun 07. pii: S0147-6513(24)00643-2. [Epub ahead of print]280 116567

Rhoptry proteins affect the placental barrier in the context of Toxoplasma gondii infection: Signaling pathways and functions.

Xinlei Wang, Lai Qu, Jie Chen, Kaisong Hu, Zhengjie Zhou, Jiaqi Zhang, Yiming An, Jingtong Zheng.

  Toxoplasma gondii is an opportunistic and pathogenic obligate intracellular parasitic protozoan that is widespread worldwide and can infect most warm-blooded animals, seriously endangering human health and affecting livestock production. Toxoplasmosis caused by T. gondii infection has different clinical manifestations, which are mainly determined by the virulence of T. gondii and host differences. Among the manifestations of this condition, abortion, stillbirth, and fetal malformation can occur if a woman is infected with T. gondii in early pregnancy. Here, we discuss how the T. gondii rhoptry protein affects host pregnancy outcomes and speculate on the related signaling pathways involved. The effects of rhoptry proteins of T. gondii on the placental barrier are complex. Rhoptry proteins not only regulate interferon-regulated genes (IRGs) to ensure the survival of parasites in activated cells but also promote the spread of worms in tissues and the invasive ability of the parasites. The functions of these rhoptry proteins and the associated signaling pathways highlight relevant mechanisms by which Toxoplasma crosses the placental barrier and influences fetal development and will guide future studies to uncover the complexity of the host-pathogen interactions.

Keywords:  Placental barrier; Rhoptry proteins; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.ecoenv.2024.116567
Parasit Vectors. 2024 Jun 10. 17(1): 252

Differential transcriptome study on the damage of testicular tissues caused by chronic infection of T. gondii in mice.

Haoxin Li, Hao Yuan, Zi-Peng Yang, Yining Song, Jun-Jie Wang, Qingyuan Wen, Yu-Xiang Zheng, Xiu-Xiang Zhang, Miao Yu, Zi-Guo Yuan.

   BACKGROUND: Toxoplasma gondii is an intracellular protozoan parasite that is widely distributed in humans and warm-blooded animals. T. gondii chronic infections can cause toxoplasmic encephalopathy, adverse pregnancy, and male reproductive disorders. In male reproduction, the main function of the testis is to provide a stable place for spermatogenesis and immunological protection. The disorders affecting testis tissue encompass abnormalities in the germ cell cycle, spermatogenic retardation, or complete cessation of sperm development. However, the mechanisms of interaction between T. gondii and the reproductive system is unclear. The aims were to study the expression levels of genes related to spermatogenesis, following T. gondii infection, in mouse testicular tissue.
METHODS: RNA-seq sequencing was carried out on mouse testicular tissues from mice infected or uninfected with the T. gondii type II Prugniaud (PRU) strain and validated in combination with real-time quantitative PCR and immunofluorescence assays.
RESULTS: The results showed that there were 250 significant differentially expressed genes (DEGs) (P < 0.05, |log2fold change| ≧ 1). Bioinformatics analysis showed that 101 DEGs were annotated to the 1696 gene ontology (GO) term. While there was a higher number of DEGs in the biological process classification as a whole, the GO enrichment revealed a significant presence of DEGs in the cellular component classification. The Arhgap18 and Syne1 genes undergo regulatory changes following T. gondii infection, and both were involved in shaping the cytoskeleton of the blood-testis barrier (BTB). The number of DEGs enriched in the MAPK signaling pathway, the ERK1/2 signaling pathway, and the JNK signaling pathway were significant. The PTGDS gene is located in the Arachidonic acid metabolism pathway, which plays an important role in the formation and maintenance of BTB in the testis. The expression of PTGDS is downregulated subsequent to T. gondii infection, potentially exerting deleterious effects on the integrity of the BTB and the spermatogenic microenvironment within the testes.
CONCLUSIONS: Overall, our research provides in-depth insights into how chronic T. gondii infection might affect testicular tissue and potentially impact male fertility. These findings offer a new perspective on the impact of T. gondii infection on the male reproductive system.

Keywords:   T. gondii chronic infection; BTB; RNA-seq; Testis

DOI:  https://doi.org/10.1186/s13071-024-06247-z
PLoS Biol. 2024 Jun 10. 22(6): e3002690

The Toxoplasma oxygen-sensing protein, TgPhyA, is required for resistance to interferon gamma-mediated nutritional immunity in mice.

Charlotte Cordonnier, Msano Mandalasi, Jason Gigley, Elizabeth A Wohlfert, Christopher M West, Ira J Blader.

As Toxoplasma gondii disseminates through its host, the parasite must sense and adapt to its environment and scavenge nutrients. Oxygen (O2) is one such environmental factor and cytoplasmic prolyl 4-hydroxylases (PHDs) are evolutionarily conserved O2 cellular sensing proteins that regulate responses to changes in O2 availability. Toxoplasma expresses 2 PHDs. One of them, TgPHYa hydroxylates SKP1, a subunit of the SCF-E3 ubiquitin ligase complex. In vitro, TgPHYa is important for growth at low O2 levels. However, studies have yet to examine the role that TgPHYa or any other pathogen-encoded PHD plays in virulence and disease. Using a type II ME49 Toxoplasma TgPHYa knockout, we report that TgPHYa is important for Toxoplasma virulence and brain cyst formation in mice. We further find that while TgPHYa mutant parasites can establish an infection in the gut, they are unable to efficiently disseminate to peripheral tissues because the mutant parasites are unable to survive within recruited immune cells. Since this phenotype was abrogated in IFNγ knockout mice, we studied how TgPHYa mediates survival in IFNγ-treated cells. We find that TgPHYa is not required for release of parasite-encoded effectors into host cells that neutralize anti-parasitic processes induced by IFNγ. In contrast, we find that TgPHYa is required for the parasite to scavenge tryptophan, which is an amino acid whose levels are decreased after IFNγ up-regulates the tryptophan-catabolizing enzyme, indoleamine dioxygenase (IDO). We further find, relative to wild-type mice, that IDO knockout mice display increased morbidity when infected with TgPHYa knockout parasites. Together, these data identify the first parasite mechanism for evading IFNγ-induced nutritional immunity and highlight a novel role that oxygen-sensing proteins play in pathogen growth and virulence.

DOI: https://doi.org/10.1371/journal.pbio.3002690
Ecohealth. 2024 Jun 08.

Evaluating the Risk Landscape of Hawaiian Monk Seal Exposure to Toxoplasma gondii.

Stacie Robinson, Kim Falinski, Devin Johnson, Elizabeth VanWormer, Karen Shapiro, Angela Amlin, Michelle Barbieri.

  Toxoplasmosis is a disease of primary concern for Hawaiian monk seals (Neomonachus schauinslandi), due to its apparently acute lethality and especially heavy impacts on breeding female seals. The disease-causing parasite, Toxoplasma gondii, depends on cats to complete its life cycle; thus, in order to understand how this pathogen infects marine mammals, it is essential to understand aspects of the terrestrial ecosystem and land-to-sea transport. In this study, we constructed a three-tiered model to assess risk of Hawaiian monk seal exposure to T. gondii oocysts: (1) oocyst contamination as a function of cat population characteristics; (2) land-to-sea transport of oocysts as a function of island hydrology, and (3) seal exposure as a function of habitat and space use. We were able to generate risk maps highlighting watersheds contributing the most to oocyst contamination of Hawaiian monk seal habitat. Further, the model showed that free-roaming cats most associated with humans (pets or strays often supplementally fed by people) were able to achieve high densities leading to high levels of oocyst contamination and elevated risk of T. gondii exposure.

Keywords:  Disease ecology; Hawaiian monk seal; Hydrology; Risk model; Toxoplasmosis

DOI:  https://doi.org/10.1007/s10393-024-01678-7
bioRxiv. 2024 May 30. pii: 2024.05.30.596652. [Epub ahead of print]

Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis.

Amanda Mixon Blackwell, Yasaman Jami-Alahmadi, Armiyaw S Nasamu, Shota Kudo, Akinobu Senoo, Celine Slam, Kouhei Tsumoto, James A Wohlschlegel, Jose M M Caaveiro, Daniel E Goldberg, Paul A Sigala.

Malaria parasites have evolved unusual metabolic adaptations that specialize them for growth within heme-rich human erythrocytes. During blood-stage infection, Plasmodium falciparum parasites internalize and digest abundant host hemoglobin within the digestive vacuole. This massive catabolic process generates copious free heme, most of which is biomineralized into inert hemozoin. Parasites also express a divergent heme oxygenase (HO)-like protein (PfHO) that lacks key active-site residues and has lost canonical HO activity. The cellular role of this unusual protein that underpins its retention by parasites has been unknown. To unravel PfHO function, we first determined a 2.8 Å-resolution X-ray structure that revealed a highly α-helical fold indicative of distant HO homology. Localization studies unveiled PfHO targeting to the apicoplast organelle, where it is imported and undergoes N-terminal processing but retains most of the electropositive transit peptide. We observed that conditional knockdown of PfHO was lethal to parasites, which died from defective apicoplast biogenesis and impaired isoprenoid-precursor synthesis. Complementation and molecular-interaction studies revealed an essential role for the electropositive N-terminus of PfHO, which selectively associates with the apicoplast genome and enzymes involved in nucleic acid metabolism and gene expression. PfHO knockdown resulted in a specific deficiency in levels of apicoplast-encoded RNA but not DNA. These studies reveal an essential function for PfHO in apicoplast maintenance and suggest that Plasmodium repurposed the conserved HO scaffold from its canonical heme-degrading function in the ancestral chloroplast to fulfill a critical adaptive role in organelle gene expression.

DOI: https://doi.org/10.1101/2024.05.30.596652
Nat Metab. 2024 Jun 13.

Coenzyme A biosynthesis: mechanisms of regulation, function and disease.

Samuel A Barritt, Sarah E DuBois-Coyne, Christian C Dibble.

The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B5), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K-AKT signalling regulate the vitamin B5 transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN).

DOI: https://doi.org/10.1038/s42255-024-01059-y
EMBO Mol Med. 2024 Jun 11.

Harnessing cholesterol uptake of malaria parasites for therapeutic applications.

Merryn Fraser, Blake Curtis, Patrick Phillips, Patrick A Yates, Kwong Sum Lam, Otto Netzel, Giel G van Dooren, Alyssa Ingmundson, Kai Matuschewski, Malcolm D McLeod, Alexander G Maier.

  Parasites, such as the malaria parasite P. falciparum, are critically dependent on host nutrients. Interference with nutrient uptake can lead to parasite death and, therefore, serve as a successful treatment strategy. P. falciparum parasites cannot synthesise cholesterol, and instead source this lipid from the host. Here, we tested whether cholesterol uptake pathways could be 'hijacked' for optimal drug delivery to the intracellular parasite. We found that fluorescent cholesterol analogues were delivered from the extracellular environment to the intracellular parasite. We investigated the uptake and inhibitory effects of conjugate compounds, where proven antimalarial drugs (primaquine and artesunate) were attached to steroids that mimic the structure of cholesterol. These conjugated antimalarial drugs improved the inhibitory effects against multiple parasite lifecycle stages, multiple parasite species, and drug-resistant parasites, whilst also lowering the toxicity to human host cells. Steroids with introduced peroxides also displayed antimalarial activity. These results provide a proof-of-concept that cholesterol mimics can be developed as a drug delivery system against apicomplexan parasites with the potential to improve drug efficacy, increase therapeutic index, and defeat drug resistance.

Keywords:   Plasmodium falciparum ; cholesterol; drug-delivery; drug-resistance; malaria

DOI:  https://doi.org/10.1038/s44321-024-00087-1
Essays Biochem. 2024 Jun 12. pii: EBC20230079. [Epub ahead of print]

Phosphorylation of mammalian cytosolic and mitochondrial malate dehydrogenase: insights into regulation.

Joseph J Provost, Kathleen A Cornely, Pamela S Mertz, Celeste N Peterson, Sophie G Riley, Harrison J Tarbox, Shree R Narasimhan, Andrew J Pulido, Amy L Springer.

  Malate dehydrogenase (MDH) is a key enzyme in mammalian metabolic pathways in cytosolic and mitochondrial compartments. Regulation of MDH through phosphorylation remains an underexplored area. In this review we consolidate evidence supporting the potential role of phosphorylation in modulating the function of mammalian MDH. Parallels are drawn with the phosphorylation of lactate dehydrogenase, a homologous enzyme, to reveal its regulatory significance and to suggest a similar regulatory strategy for MDH. Comprehensive mining of phosphorylation databases, provides substantial experimental (primarily mass spectrometry) evidence of MDH phosphorylation in mammalian cells. Experimentally identified phosphorylation sites are overlaid with MDH's functional domains, offering perspective on how these modifications could influence enzyme activity. Preliminary results are presented from phosphomimetic mutations (serine/threonine residues changed to aspartate) generated in recombinant MDH proteins serving as a proof of concept for the regulatory impact of phosphorylation. We also examine and highlight several approaches to probe the structural and cellular impact of phosphorylation. This review highlights the need to explore the dynamic nature of MDH phosphorylation and calls for identifying the responsible kinases and the physiological conditions underpinning this modification. The synthesis of current evidence and experimental data aims to provide insights for future research on understanding MDH regulation, offering new avenues for therapeutic interventions in metabolic disorders and cancer.

Keywords:  MDH; kinase; malate dehydrogenase; metabolism; phosphorylation; post translational modification

DOI:  https://doi.org/10.1042/EBC20230079
Cell Div. 2024 Jun 12. 19(1): 20

Advances in SIRT3 involvement in regulating autophagy-related mechanisms.

Shuangyun Xi, Weijun Chen, Yong Ke.

  The silencing regulatory factor 2-like protein 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent deacetylase located primarily in the mitochondria. This protein plays an important role in oxidative stress, energy metabolism, and autophagy in multicellular organisms. Autophagy (macroautophagy) is primarily a cytoprotective mechanism necessary for intracellular homeostasis and the synthesis, degradation, and recycling of cellular products. Autophagy can influence the progression of several neural, cardiac, hepatic, and renal diseases and can also contribute to the development of fibrosis, diabetes, and many types of cancer. Recent studies have shown that SIRT3 has an important role in regulating autophagy. Therefore in this study, we aimed to perform a literature review to summarize the role of SIRT3 in the regulation of cellular autophagy. The findings of this study could be used to identify new drug targets for SIRT3-related diseases. Methods: A comprehensive literature review of the mechanism involved behind SIRT3 and autophagy-related diseases was performed. Relevant literature published in Pubmed and Web of Science up to July 2023 was identified using the keywords "silencing regulatory factor 2-like protein 3", "SIRT3" and "autophagy".

Keywords:  Autophagy; Deacetylase; SIRT3; Signaling pathway

DOI:  https://doi.org/10.1186/s13008-024-00124-y
Microb Cell Fact. 2024 Jun 12. 23(1): 173

Citrate synthase variants improve yield of acetyl-CoA derived 3-hydroxybutyrate in Escherichia coli.

Hemshikha Rajpurohit, Mark A Eiteman.

   BACKGROUND: The microbial chiral product (R)-3-hydroxybutyrate (3-HB) is a gateway to several industrial and medical compounds. Acetyl-CoA is the key precursor for 3-HB, and several native pathways compete with 3-HB production. The principal competing pathway in wild-type Escherichia coli for acetyl-CoA is mediated by citrate synthase (coded by gltA), which directs over 60% of the acetyl-CoA into the tricarboxylic acid cycle. Eliminating citrate synthase activity (deletion of gltA) prevents growth on glucose as the sole carbon source. In this study, an alternative approach is used to generate an increased yield of 3-HB: citrate synthase activity is reduced but not eliminated by targeted substitutions in the chromosomally expressed enzyme.
RESULTS: Five E. coli GltA variants were examined for 3-HB production via heterologous overexpression of a thiolase (phaA) and NADPH-dependent acetoacetyl-CoA reductase (phaB) from Cupriavidus necator. In shake flask studies, four variants showed nearly 5-fold greater 3-HB yield compared to the wild-type, although pyruvate accumulated. Overexpression of either native thioesterases TesB or YciA eliminated pyruvate formation, but diverted acetyl-CoA towards acetate formation. Overexpression of pantothenate kinase similarly decreased pyruvate formation but did not improve 3-HB yield. Controlled batch studies at the 1.25 L scale demonstrated that the GltA[A267T] variant produced the greatest 3-HB titer of 4.9 g/L with a yield of 0.17 g/g. In a phosphate-starved repeated batch process, E. coli ldhA poxB pta-ackA gltA::gltA[A267T] generated 15.9 g/L 3-HB (effective concentration of 21.3 g/L with dilution) with yield of 0.16 g/g from glucose as the sole carbon source.
CONCLUSIONS: This study demonstrates that GltA variants offer a means to affect the generation of acetyl-CoA derived products. This approach should benefit a wide range of acetyl-CoA derived biochemical products in E. coli and other microbes. Enhancing substrate affinity of the introduced pathway genes like thiolase towards acetyl-CoA will likely further increase the flux towards 3-HB while reducing pyruvate and acetate accumulation.

Keywords:  3-hydroxybutyrate; Batch; Fermentation; Point mutation; Repeated batch

DOI:  https://doi.org/10.1186/s12934-024-02444-8
Expert Opin Ther Pat. 2024 Jun 14.

HDAC3 inhibitors: a patent review of their broad-spectrum applications as therapeutic agents.

Thabo Brighton Makgoba, Erika Kapp, Samuel Egieyeh, Jacques Joubert.

   INTRODUCTION: Histone deacetylases (HDACs) are a class of zinc-dependent enzymes. They maintain acetylation homeostasis, with numerous biological functions and are associated with many diseases. HDAC3 strictly requires multi-subunit complex formation for activity. It is associated with the progression of numerous non-communicable diseases. Its widespread involvement in diseases makes it an epigenetic drug target. Preexisting HDAC3 inhibitors have many uses, highlighting the need for continued research in the discovery of HDAC3-selective inhibitors.
AREA COVERED: This review provides an overview of 24 patents published from 2010-2023, focusing on compounds that inhibit the HDAC3 isoenzyme.
EXPERT OPINION: HDAC3-selective inhibitors - pivotal for pharmacological application as single or combination therapies - are gaining traction as a strategy to move away from complications laden pan-HDAC inhibitors. Moreover, there is an unmet need for HDAC3 inhibitors with alternative zinc-binding groups (ZBG) because some preexisting ZBGs have limitations related to toxicity and side effects. Difficulties in achieving HDAC3 selectivity may be due to isoform selectivity. However, advancements in computer-aided drug design and experimental data of HDAC3 3D co-crystallized models could lead to discovery of novel HDAC3-selective inhibitors. Which bear alternative ZBGs with balanced selectivity for HDAC3 and potency.

Keywords:  HDAC3; HDAC3-selective inhibitors; HDACs; Therapeutic applications

DOI:  https://doi.org/10.1080/13543776.2024.2363890
bioRxiv. 2024 May 28. pii: 2024.05.28.596234. [Epub ahead of print]

Active E. coli heteromeric acetyl-CoA carboxylase forms polymorphic helical tubular filaments.

Xueyong Xu, Amanda Silva de Sousa, Trevor J Boram, Wen Jiang, Jeremy R Lohman.

The Escherichia coli heteromeric acetyl-CoA carboxylase (ACC) has four subunits assumed to form an elusive catalytic complex and are involved in allosteric and transcriptional regulation. The E. coli ACC represents almost all ACCs from pathogenic bacteria making it a key antibiotic development target to fight growing antibiotic resistance. Furthermore, it is a model for cyanobacterial and plant plastid ACCs as biofuel engineering targets. Here we report the catalytic E. coli ACC complex surprisingly forms tubes rather than dispersed particles. The cryo-EM structure reveals key protein-protein interactions underpinning efficient catalysis and how transcriptional regulatory roles are masked during catalysis. Discovering the protein-protein interaction interfaces that facilitate catalysis, allosteric and transcriptional regulation provides new routes to engineering catalytic activity and new targets for drug discovery.
One-Sentence Summary: Bacterial heteromeric acetyl-CoA carboxylase forms tubes to promote efficient catalysis and mask transcriptional regulation.

DOI: https://doi.org/10.1101/2024.05.28.596234
Commun Biol. 2024 Jun 08. 7(1): 704

Sirtuin E deacetylase is required for full virulence of Aspergillus fumigatus.

Natália S Wassano, Gabriela B da Silva, Artur H Reis, Jaqueline A Gerhardt, Everton P Antoniel, Daniel Akiyama, Caroline P Rezende, Leandro X Neves, Elton J R Vasconcelos, Fernanda L de Figueiredo, Fausto Almeida, Patrícia A de Castro, Camila F Pinzan, Gustavo H Goldman, Adriana F Paes Leme, Taicia P Fill, Nilmar S Moretti, André Damasio.

Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates. Protein acetylation is a crucial post-translational modification that controls gene expression and biological processes. The strategic manipulation of enzymes involved in protein acetylation has emerged as a promising therapeutic approach for addressing fungal infections. Sirtuins, NAD+-dependent lysine deacetylases, regulate protein acetylation and gene expression in eukaryotes. However, their role in the human pathogenic fungus A. fumigatus remains unclear. This study constructs six single knockout strains of A. fumigatus and a strain lacking all predicted sirtuins (SIRTKO). The mutant strains are viable under laboratory conditions, indicating that sirtuins are not essential genes. Phenotypic assays suggest sirtuins' involvement in cell wall integrity, secondary metabolite production, thermotolerance, and virulence. Deletion of sirE attenuates virulence in murine and Galleria mellonella infection models. The absence of SirE alters the acetylation status of proteins, including histones and non-histones, and triggers significant changes in the expression of genes associated with secondary metabolism, cell wall biosynthesis, and virulence factors. These findings encourage testing sirtuin inhibitors as potential therapeutic strategies to combat A. fumigatus infections or in combination therapy with available antifungals.

DOI: https://doi.org/10.1038/s42003-024-06383-3
Open Biol. 2024 Jun;14(6): 230451

Plasmodium LCCL domain-containing modular proteins have their origins in the ancestral alveolate.

Callum De Hoest-Thompson, Virginia Marugan-Hernandez, Johannes T Dessens.

  Plasmodium species encode a unique set of six modular proteins named LCCL lectin domain adhesive-like proteins (LAPs) that operate as a complex and that are essential for malaria parasite transmission from mosquito to vertebrate. LAPs possess complex architectures obtained through unique assemblies of conserved domains associated with lipid, protein and carbohydrate interactions, including the name-defining LCCL domain. Here, we assessed the prevalence of Plasmodium LAP orthologues across eukaryotic life. Our findings show orthologous conservation in all apicomplexans, with lineage-specific repertoires acquired through differential lap gene loss and duplication. Besides Apicomplexa, LAPs are found in their closest relatives: the photosynthetic chromerids, which encode the broadest repertoire including a novel membrane-bound LCCL protein. LAPs are notably absent from other alveolate lineages (dinoflagellates, perkinsids and ciliates), but are encoded by predatory colponemids, a sister group to the alveolates. These results reveal that the LAPs are much older than previously thought and pre-date not only the Apicomplexa but the Alveolata altogether.

Keywords:  Alveolata; Apicomplexa; Colpenemida; malaria

DOI:  https://doi.org/10.1098/rsob.230451
Mini Rev Med Chem. 2024 Jun 07.

Insight in Quinazoline-based HDAC Inhibitors as Anti-cancer Agents.

Elena Martino, Shruti Thakur, Arun Kumar, Ashok Kumar Yadav, Donatella Boschi, Deepak Kumar, Marco Lolli.

  Cancer remains a primary cause of death globally, and effective treatments are still limited. While chemotherapy has notably enhanced survival rates, it brings about numerous side effects. Consequently, the ongoing challenge persists in developing potent anti-cancer agents with minimal toxicity. The versatile nature of the quinazoline moiety has positioned it as a pivotal component in the development of various antitumor agents, showcasing its promising role in innovative cancer therapeutics. This concise review aims to reveal the potential of quinazolines in creating anticancer medications that target histone deacetylases (HDACs).

Keywords:  HDAC inhibitors; Quinazoline; anti-proliferative agents; cancer; hybrid HDAC inhibitors; multitarget approach

DOI:  https://doi.org/10.2174/0113895575303614240527093106
Essays Biochem. 2024 Jun 12. pii: EBC20230088. [Epub ahead of print]

Malate dehydrogenase (MDH) in cancer: a promiscuous enzyme, a redox regulator, and a metabolic co-conspirator.

Betsy Leverett, Shane Austin, Jason Tan-Arroyo.

  Malate dehydrogenase (MDH) is an essential enzyme in the tricarboxylic acid cycle that functions in cellular respiration and redox homeostasis. Recent studies indicate that MDH facilitates metabolic plasticity in tumor cells, catalyzing the formation of an oncometabolite, contributing to altered epigenetics, and maintaining redox capacity to support the rewired energy metabolism and biosynthesis that enables cancer progression. This minireview summarizes current findings on the unique supporting roles played by MDH in human cancers and provides an update on targeting MDH in cancer chemotherapy.

Keywords:  cancer; malate dehydrogenase; metabolomics; oncometabolism; redox balance

DOI:  https://doi.org/10.1042/EBC20230088
Biomed Pharmacother. 2024 Jun 12. pii: S0753-3322(24)00806-0. [Epub ahead of print]176 116922

A systematic review of epigenetic interplay in kidney diseases: Crosstalk between long noncoding RNAs and methylation, acetylation of chromatin and histone.

Rui-Zhi Tan, Jian Jia, Tong Li, Li Wang, Fahsai Kantawong.

  The intricate crosstalk between long noncoding RNAs (lncRNAs) and epigenetic modifications such as chromatin/histone methylation and acetylation offer new perspectives on the pathogenesis and treatment of kidney diseases. lncRNAs, a class of transcripts longer than 200 nucleotides with no protein-coding potential, are now recognized as key regulatory molecules influencing gene expression through diverse mechanisms. They modulate the epigenetic modifications by recruiting or blocking enzymes responsible for adding or removing methyl or acetyl groups, such as DNA, N6-methyladenosine (m6A) and histone methylation and acetylation, subsequently altering chromatin structure and accessibility. In kidney diseases such as acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), glomerulonephritis (GN), and renal cell carcinoma (RCC), aberrant patterns of DNA/RNA/histone methylation and acetylation have been associated with disease onset and progression, revealing a complex interplay with lncRNA dynamics. Recent studies have highlighted how lncRNAs can impact renal pathology by affecting the expression and function of key genes involved in cell cycle control, fibrosis, and inflammatory responses. This review will separately address the roles of lncRNAs and epigenetic modifications in renal diseases, with a particular emphasis on elucidating the bidirectional regulatory effects and underlying mechanisms of lncRNAs in conjunction with DNA/RNA/histone methylation and acetylation, in addition to the potential exacerbating or renoprotective effects in renal pathologies. Understanding the reciprocal relationships between lncRNAs and epigenetic modifications will not only shed light on the molecular underpinnings of renal pathologies but also present new avenues for therapeutic interventions and biomarker development, advancing precision medicine in nephrology.

Keywords:  Acetylation; Epigenetic; Kidney diseases; LncRNA; Methylation

DOI:  https://doi.org/10.1016/j.biopha.2024.116922
Front Cell Dev Biol. 2024 ;12 1368171

Emerging role of HDAC11 in skeletal muscle biology.

Jihong Chen, Qiao Li.

  HDAC11 is an epigenetic repressor of gene transcription, acting through its deacetylase activity to remove functional acetyl groups from the lysine residues of histones at genomic loci. It has been implicated in the regulation of different immune responses, metabolic activities, as well as cell cycle progression. Recent studies have also shed lights on the impact of HDAC11 on myogenic differentiation and muscle development, indicating that HDAC11 is important for histone deacetylation at the promoters to inhibit transcription of cell cycle related genes, thereby permitting myogenic activation at the onset of myoblast differentiation. Interestingly, the upstream networks of HDAC11 target genes are mainly associated with cell cycle regulators and the acetylation of histones at the HDAC11 target promoters appears to be residue specific. As such, selective inhibition, or activation of HDAC11 presents a potential therapeutic approach for targeting distinct epigenetic pathways in clinical applications.

Keywords:  chromatin modification; gene regulation; histone acetylation; histone deacetylase; myogenic differentiation

DOI:  https://doi.org/10.3389/fcell.2024.1368171
Hortic Res. 2024 Jun;11(6): uhae099

The critical roles of three sugar-related proteins (HXK, SnRK1, TOR) in regulating plant growth and stress responses.

Guangshuo Li, Ying Zhao.

Sugar signaling is one of the most critical regulatory signals in plants, and its metabolic network contains multiple regulatory factors. Sugar signal molecules regulate cellular activities and organism development by combining with other intrinsic regulatory factors and environmental inputs. HXK, SnRK1, and TOR are three fundamental proteins that have a pivotal role in the metabolism of sugars in plants. HXK, being the initial glucose sensor discovered in plants, is renowned for its multifaceted characteristics. Recent investigations have unveiled that HXK additionally assumes a significant role in plant hormonal signaling and abiotic stress. SnRK1 serves as a vital regulator of growth under energy-depleted circumstances, whereas TOR, a large protein, acts as a central integrator of signaling pathways that govern cell metabolism, organ development, and transcriptome reprogramming in response to diverse stimuli. Together, these two proteins work to sense upstream signals and modulate downstream signals to regulate cell growth and proliferation. In recent years, there has been an increasing amount of research on these three proteins, particularly on TOR and SnRK1. Furthermore, studies have found that these three proteins not only regulate sugar signaling but also exhibit certain signal crosstalk in regulating plant growth and development. This review provides a comprehensive overview and summary of the basic functions and regulatory networks of these three proteins. It aims to serve as a reference for further exploration of the interactions between these three proteins and their involvement in co-regulatory networks.

DOI: https://doi.org/10.1093/hr/uhae099
Clin Epigenetics. 2024 Jun 11. 16(1): 78

Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues.

Kukkala Kiran Kumar, Elhadi Husein Aburawi, Milos Ljubisavljevic, Melvin Khee Shing Leow, Xu Feng, Suraiya Anjum Ansari, Bright Starling Emerald.

  Diabetes mellitus is a chronic disease that impairs metabolism, and its prevalence has reached an epidemic proportion globally. Most people affected are with type 2 diabetes mellitus (T2DM), which is caused by a decline in the numbers or functioning of pancreatic endocrine islet cells, specifically the β-cells that release insulin in sufficient quantity to overcome any insulin resistance of the metabolic tissues. Genetic and epigenetic factors have been implicated as the main contributors to the T2DM. Epigenetic modifiers, histone deacetylases (HDACs), are enzymes that remove acetyl groups from histones and play an important role in a variety of molecular processes, including pancreatic cell destiny, insulin release, insulin production, insulin signalling, and glucose metabolism. HDACs also govern other regulatory processes related to diabetes, such as oxidative stress, inflammation, apoptosis, and fibrosis, revealed by network and functional analysis. This review explains the current understanding of the function of HDACs in diabetic pathophysiology, the inhibitory role of various HDAC inhibitors (HDACi), and their functional importance as biomarkers and possible therapeutic targets for T2DM. While their role in T2DM is still emerging, a better understanding of the role of HDACi may be relevant in improving insulin sensitivity, protecting β-cells and reducing T2DM-associated complications, among others.

Keywords:  Diabetes mellitus; Functional analysis; HDAC inhibitors; HDACs; Insulin; Pancreatic β-cells

DOI:  https://doi.org/10.1186/s13148-024-01692-0
Genomics Proteomics Bioinformatics. 2024 May 09. pii: qzae019. [Epub ahead of print]22(1):

Substrate and Functional Diversity of Protein Lysine Post-translational Modifications.

Bingbing Hao, Kaifeng Chen, Linhui Zhai, Muyin Liu, Bin Liu, Minjia Tan.

  Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins. Dysregulation of lysine PTMs is implicated in many diseases, and targeting lysine PTM regulatory factors, including writers, erasers, and readers, has become an effective strategy for disease therapy. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs. The global characterization of lysine PTMs is crucial for deciphering the regulatory networks, molecular functions, and mechanisms of action of lysine PTMs. In this review, we focus on lysine PTMs, and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies. We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.

Keywords:  Acylation; Drug target; PTM crosstalk; Protein lysine PTM; Regulatory enzyme

DOI:  https://doi.org/10.1093/gpbjnl/qzae019
Proc Natl Acad Sci U S A. 2024 Jun 18. 121(25): e2409269121

SIRT7 promotes lung cancer progression by destabilizing the tumor suppressor ARF.

Poonam Kumari, Shahriar Tarighi, Eva Fuchshuber, Luhan Li, Irene Fernández-Duran, Meilin Wang, Joshua Ayoson, Jose Manuel Castelló-García, Andrés Gámez-García, Maria Espinosa-Alcantud, Krishnamoorthy Sreenivasan, Stefan Guenther, Mireia Olivella, Rajkumar Savai, Shijing Yue, Alejandro Vaquero, Thomas Braun, Alessandro Ianni.

  Sirtuin 7 (SIRT7) is a member of the mammalian family of nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylases, known as sirtuins. It acts as a potent oncogene in numerous malignancies, but the molecular mechanisms employed by SIRT7 to sustain lung cancer progression remain largely uncharacterized. We demonstrate that SIRT7 exerts oncogenic functions in lung cancer cells by destabilizing the tumor suppressor alternative reading frame (ARF). SIRT7 directly interacts with ARF and prevents binding of ARF to nucleophosmin, thereby promoting proteasomal-dependent degradation of ARF. We show that SIRT7-mediated degradation of ARF increases expression of protumorigenic genes and stimulates proliferation of non-small-cell lung cancer (NSCLC) cells both in vitro and in vivo in a mouse xenograft model. Bioinformatics analysis of transcriptome data from human lung adenocarcinomas revealed a correlation between SIRT7 expression and increased activity of genes normally repressed by ARF. We propose that disruption of SIRT7-ARF signaling stabilizes ARF and thus attenuates cancer cell proliferation, offering a strategy to mitigate NSCLC progression.

Keywords:  ARF; SIRT7; Sirtuins; lung cancer; nucleophosmin

DOI:  https://doi.org/10.1073/pnas.2409269121
Stem Cells. 2024 Jun 12. pii: sxae041. [Epub ahead of print]

Epigenetically Rewiring Metabolic Genes via SIRT6 Orchestrates MSC Fate Determination.

Xueyang Liao, Feifei Li, Fanyuan Yu, Ling Ye.

  SIRT6 owns versatile types of enzymatic activities as a multitasking protein, including ribosyltransferase and deacetylase ones. To investigate the epigenetic regulations of SIRT6 on MSC fate determination via histone deacetylation, we utilized allosteric small molecules specifically controlling its histone 3 deacetylation activities. Results showed that enhanced deacetylation of SIRT6 promoted the ossific lineage commitment of MSC and finally achieved anabolic effects on hard tissues. Mechanistically, H3K9ac and H3K56ac, governed by SIRT6, in MSC orchestrated the transcriptions of crucial metabolic genes, mediating MSC fate determination. Most importantly, our data evidenced that modulating the epigenetic regulations of SIRT6, specifically via enhancing its deacetylation of H3K9ac and H3K56ac, was a promising choice to treat bone loss diseases and promote dentine regeneration. In this study, we revealed the specific roles of SIRT6's histone modification in MSC fate determination. These findings endow us with insights on SIRT6 and the promising therapeutic choices through SIRT6's epigenetic functions for hard tissues regeneration.

Keywords:  Hard tissues; Mesenchymal stem cell; Odontoblastogenesis; Osteogenesis; Sirtuin 6

DOI:  https://doi.org/10.1093/stmcls/sxae041
Curr Opin Plant Biol. 2024 Jun 13. pii: S1369-5266(24)00063-3. [Epub ahead of print]81 102572

Epigenetic control of gene expression by cellular metabolisms in plants.

Fei Huang, Yuehui He.

  Covalent modifications on DNA and histones can regulate eukaryotic gene expression and are often referred to as epigenetic modifications. These chemical reactions require various metabolites as donors or co-substrates, such as acetyl coenzyme A, S-adenosyl-l-methionine, and α-ketoglutarate. Metabolic processes that take place in the cytoplasm, nucleus, or other cellular compartments may impact epigenetic modifications in the nucleus. Here, we review recent advances on metabolic control of chromatin modifications and thus gene expression in plants, with a focus on the functions of nuclear compartmentalization of metabolic processes and enzymes in DNA and histone modifications. Furthermore, we discuss the functions of cellular metabolisms in fine-tuning gene expression to facilitate the responses or adaptation to environmental changes in plants.

Keywords:  Cellular metabolism; Chromatin modification; DNA methylation; Gene expression; Nuclear metabolite

DOI:  https://doi.org/10.1016/j.pbi.2024.102572
Cold Spring Harb Perspect Med. 2024 Jun 10. pii: a041544. [Epub ahead of print]

Metabolic Signaling in Cancer.

Laura V Pinheiro, Pedro Costa-Pinheiro, Kathryn E Wellen.

Metabolic reprogramming in cancer allows cells to survive in harsh environments and sustain macromolecular biosynthesis to support proliferation. In addition, metabolites play crucial roles as signaling molecules. Metabolite fluctuations are detected by various sensors in the cell to regulate gene expression, metabolism, and signal transduction. Metabolic signaling mechanisms contribute to tumorigenesis by altering the physiology of cancer cells themselves, as well as that of neighboring cells in the tumor microenvironment. In this review, we discuss principles of metabolic signaling and provide examples of how cancer cells take advantage of metabolic signals to promote cell proliferation and evade the immune system, thereby contributing to tumor growth and progression.

DOI: https://doi.org/10.1101/cshperspect.a041544
Nat Commun. 2024 Jun 08. 15(1): 4913

SOD3 suppresses early cellular immune responses to parasite infection.

Qilong Li, Kunying Lv, Ning Jiang, Tong Liu, Nan Hou, Liying Yu, Yixin Yang, Anni Feng, Yiwei Zhang, Ziwei Su, Xiaoyu Sang, Ying Feng, Ran Chen, Wenyue Xu, Liwang Cui, Yaming Cao, Qijun Chen.

Host immune responses are tightly controlled by various immune factors during infection, and protozoan parasites also manipulate the immune system to evade surveillance, leading to an evolutionary arms race in host‒pathogen interactions; however, the underlying mechanisms are not fully understood. We observed that the level of superoxide dismutase 3 (SOD3) was significantly elevated in both Plasmodium falciparum malaria patients and mice infected with four parasite species. SOD3-deficient mice had a substantially longer survival time and lower parasitemia than control mice after infection, whereas SOD3-overexpressing mice were much more vulnerable to parasite infection. We revealed that SOD3, secreted from activated neutrophils, bound to T cells, suppressed the interleukin-2 expression and concomitant interferon-gamma responses crucial for parasite clearance. Overall, our findings expose active fronts in the arms race between the parasites and host immune system and provide insights into the roles of SOD3 in shaping host innate immune responses to parasite infection.

DOI: https://doi.org/10.1038/s41467-024-49348-0
Nat Commun. 2024 Jun 11. 15(1): 4962

Acetylation of histones and non-histone proteins is not a mere consequence of ongoing transcription.

Tim Liebner, Sinan Kilic, Jonas Walter, Hitoshi Aibara, Takeo Narita, Chunaram Choudhary.

In all eukaryotes, acetylation of histone lysine residues correlates with transcription activation. Whether histone acetylation is a cause or consequence of transcription is debated. One model suggests that transcription promotes the recruitment and/or activation of acetyltransferases, and histone acetylation occurs as a consequence of ongoing transcription. However, the extent to which transcription shapes the global protein acetylation landscapes is not known. Here, we show that global protein acetylation remains virtually unaltered after acute transcription inhibition. Transcription inhibition ablates the co-transcriptionally occurring ubiquitylation of H2BK120 but does not reduce histone acetylation. The combined inhibition of transcription and CBP/p300 further demonstrates that acetyltransferases remain active and continue to acetylate histones independently of transcription. Together, these results show that histone acetylation is not a mere consequence of transcription; acetyltransferase recruitment and activation are uncoupled from the act of transcription, and histone and non-histone protein acetylation are sustained in the absence of ongoing transcription.

DOI: https://doi.org/10.1038/s41467-024-49370-2
ACS Org Inorg Au. 2024 Jun 05. 4(3): 319-328

Zinc(II) Complexes of SIRTi1/2 Analogues Transmetallating with Copper Ions and Inducing ROS Mediated Paraptosis.

Ashwini Kumar, Ayushi Chaudhary, Himanshu Sonker, Seemadri Subhadarshini, Mohit K Jolly, Ritika Gautam Singh.

As the SIRTi analogue series (HL1-HL6) show potent antitumor activity in vitro, we synthesized their corresponding zinc(II) complexes (ZnL1-ZnL6) and investigated their potential as anticancer agents. The Zn(II) complexes showed substantially greater cytotoxicity than HL1-HL6 alone in several cancer cell-types. Notably, distinct structure-activity relationships confirmed the significance of tert-butyl (ZnL2) pharmacophore inclusion in their activity. ZnL2 complexes were found to transmetalate with copper ions inside cells, causing the formation of redox-active copper complexes that induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, ATP decay, and cell death. This is the first study to exhibit Zn(II) complexes that mediate their activity via transmetalation with copper ions to undergo paraptosis cell death pathway. To further confirm if the SIRT1/2 inhibitory property of SIRTi analogues is conserved, a docking simulation study is performed. The binding affinity and specific interactions of the Cu(II) complex obtained after transmetalation with ZnL2 were found to be higher for SIRT2 (K i = 0.06 μM) compared to SIRT1 (K i = 0.25 μM). Thus, the concurrent regulation of several biological targets using a single drug has been shown to have synergistic therapeutic effects, which are crucial for the effective treatment of cancer.

DOI: https://doi.org/10.1021/acsorginorgau.3c00052