bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2023–08–20
nine papers selected by
Lakesh Kumar, BITS Pilani
  1. The apicoplast is important for the viability and persistence of Toxoplasma gondii bradyzoites.
  2. Interplay of energy metabolism and autophagy.
  3. Functional Diversity of SIRT7 Across Cellular Compartments: Insights and Perspectives.
  4. NAD(P) transhydrogenase isoform distribution provides insight into apicomplexan evolution.
  5. Author Correction: A positive feedback loop controls Toxoplasma chronic differentiation.
  6. Autophagy contributes to positive feedback regulation of SnRK1 signaling in plants.
  7. Host nutrient sensing is mediated by mTOR signaling in cnidarian-dinoflagellate symbiosis.
  8. The RNA-binding protein RBP42 regulates cellular energy metabolism in mammalian-infective Trypanosoma brucei.
  9. Post-translational modifications of ATG8 proteins - an emerging mechanism of autophagy control.
  1. Proc Natl Acad Sci U S A. 2023 Aug 22. 120(34): e2309043120
    The apicoplast is important for the viability and persistence of Toxoplasma gondii bradyzoites.
    Syrian G Sanchez, Emilie Bassot, Aude Cerutti, Hoa Mai Nguyen, Amel Aïda, Nicolas Blanchard, Sébastien Besteiro.
      Toxoplasma gondii is responsible for toxoplasmosis, a disease that can be serious when contracted during pregnancy, but can also be a threat for immunocompromised individuals. Acute infection is associated with the tachyzoite form that spreads rapidly within the host. However, under stress conditions, some parasites can differentiate into cyst-forming bradyzoites, residing mainly in the central nervous system, retina and muscle. Because this latent form of the parasite is resistant to all currently available treatments, and is central to persistence and transmission of the parasite, specific therapeutic strategies targeting this developmental stage need to be found. T. gondii contains a plastid of endosymbiotic origin called the apicoplast, which is an appealing drug target because it is essential for tachyzoite viability and contains several key metabolic pathways that are largely absent from the mammalian host. Its function in bradyzoites, however, is unknown. Our objective was thus to study the contribution of the apicoplast to the viability and persistence of bradyzoites during chronic toxoplasmosis. We have used complementary strategies based on stage-specific promoters to generate conditional bradyzoite mutants of essential apicoplast genes. Our results show that specifically targeting the apicoplast in both in vitro or in vivo-differentiated bradyzoites leads to a loss of long-term bradyzoite viability, highlighting the importance of this organelle for this developmental stage. This validates the apicoplast as a potential area to look for therapeutic targets in bradyzoites, with the aim to interfere with this currently incurable parasite stage.
    Keywords:  Toxoplasma gondii; chronic toxoplasmosis; plastid; stage differentiation
    DOI:  https://doi.org/10.1073/pnas.2309043120
  2. Autophagy. 2023 Aug 18. 1-11
    Interplay of energy metabolism and autophagy.
    Yuyao Feng, Ying Chen, Xiaoyong Wu, Junye Chen, Qingyan Zhou, Bao Liu, Liqin Zhang, Cong Yi.
      Macroautophagy/autophagy, is widely recognized for its crucial role in enabling cell survival and maintaining cellular energy homeostasis during starvation or energy stress. Its regulation is intricately linked to cellular energy status. In this review, covering yeast, mammals, and plants, we aim to provide a comprehensive overview of the understanding of the roles and mechanisms of carbon- or glucose-deprivation related autophagy, showing how cells effectively respond to such challenges for survival. Further investigation is needed to determine the specific degraded substrates by autophagy during glucose or energy deprivation and the diverse roles and mechanisms during varying durations of energy starvation.Abbreviations: ADP: adenosine diphosphate; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GD: glucose deprivation; GFP: green fluorescent protein; GTPases: guanosine triphosphatases; HK2: hexokinase 2; K phaffii: Komagataella phaffii; LD: lipid droplet; MAP1LC3/LC3: microtubule-associated protein1 light chain 3; MAPK: mitogen-activated protein kinase; Mec1: mitosis entry checkpoint 1; MTOR: mechanistic target of rapamycin kinase; NAD (+): nicotinamide adenine dinucleotide; OGD: oxygen and glucose deprivation; PAS: phagophore assembly site; PCD: programmed cell death; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; ROS: reactive oxygen species; S. cerevisiae: Saccharomyces cerevisiae; SIRT1: sirtuin 1; Snf1: sucrose non-fermenting 1; STK11/LKB1: serine/threonine kinase 11; TFEB: transcription factor EB; TORC1: target of rapamycin complex 1; ULK1: unc-51 like kinase 1; Vps27: vacuolar protein sorting 27; Vps4: vacuolar protein sorting 4.
    Keywords:  AMPK; Snf1; autophagy; carbon starvation; energy metabolism; glucose starvation
    DOI:  https://doi.org/10.1080/15548627.2023.2247300
  3. Cell Biochem Biophys. 2023 Aug 15.
    Functional Diversity of SIRT7 Across Cellular Compartments: Insights and Perspectives.
    Songtao Wu, Shengnan Jia.
      Posttranslational modifications (PTMs) play important roles in the regulation of protein function. Acetylation and deacetylation are among the most important PTMs. SIRT7 is a relatively understudied member of the sirtuin family, but recent studies have revealed that it plays a regulatory role in a variety of cellular activities, such as genome stabilization and repair, gene translation, ribosome production and other important processes. Here, we provide a list of the functions and mechanisms of SIRT7 in various organelles and show the important role of SIRT7 in maintaining normal cell function.
    Keywords:  Cell metabolism; Deacetylation; Genome stability; SIRT7; Transcription
    DOI:  https://doi.org/10.1007/s12013-023-01162-z
  4. Front Ecol Evol. 2023 Jun 28. pii: fevo.2023.1216385. [Epub ahead of print]11
    NAD(P) transhydrogenase isoform distribution provides insight into apicomplexan evolution.
    Annie Z Tremp, Sadia Saeed, Johannes T Dessens.
      Membrane-located NAD(P) transhydrogenase (NTH) catalyses reversible hydride ion transfer between NAD(H) and NADP(H), simultaneously translocating a proton across the membrane. The enzyme is structurally conserved across prokaryotes and eukaryotes. In heterotrophic bacteria NTH proteins reside in the cytoplasmic membrane, whereas in animals they localise in the mitochondrial inner membrane. Eukaryotic NTH proteins exists in two distinct configurations (isoforms) and have non-mitochondrial functions in unicellular eukaryotes like Plasmodium, the causative agent of malaria. In this study, we carried out a systematic analysis of nth genes across eukaryotic life to determine its prevalence and distribution of isoforms. The results reveal that NTH is found across all major lineages, but that some organisms, notably plants, lack nth genes altogether. Isoform distribution and phylogenetic analysis reveals different nth gene loss scenarios in apicomplexan lineages, which sheds new light on the evolution of the Piroplasmida and Eimeriidae.
    Keywords:  Apicomplexa; Plasmodium; TSAR; Transhydrogenase; alveolates; isoform
    DOI:  https://doi.org/10.3389/fevo.2023.1216385
  5. Nat Microbiol. 2023 Aug 15.
    Author Correction: A positive feedback loop controls Toxoplasma chronic differentiation.
    M Haley Licon, Christopher J Giuliano, Alex W Chan, Sundeep Chakladar, Julia N Eberhard, Lindsey A Shallberg, Sambamurthy Chandrasekaran, Benjamin S Waldman, Anita A Koshy, Christopher A Hunter, Sebastian Lourido.
      
    DOI:  https://doi.org/10.1038/s41564-023-01467-y
  6. Autophagy. 2023 Aug 16.
    Autophagy contributes to positive feedback regulation of SnRK1 signaling in plants.
    Chao Yang, Xibao Li, Jun Zhou, Caiji Gao.
      SnRK1 (SNF1-related protein kinase 1) is a plant ortholog of yeast Snf1 and mammalian adenosine monophosphate-activated protein kinase (AMPK) that acts as a positive regulator of macroautophagy/autophagy. However, whether and how the autophagy pathway modulates SnRK1 activity remains elusive. Recently, we identified a clade of plant-specific FLZ (FCS-like zinc finger) proteins as novel ATG8 (autophagy related 8)-interacting partners in Arabidopsis thaliana. These AtFLZs, which mainly localize on the surface of mitochondria, can inhibit SnRK1 signaling by repressing the T-loop phosphorylation of its catalytic α subunits, thereby negatively regulating carbon starvation-induced autophagy and plant tolerance to energy deprivation. Upon energy starvation, autophagy is activated to mediate the degradation of these AtFLZs, thus relieving their repression of SnRK1. More importantly, the ATG8-FLZ-SnRK1 regulatory axis appears to be functionally conserved during seed plant evolution. These findings highlight the positive role of autophagy in SnRK1 signaling activation under energy-limiting conditions in plants.
    Keywords:  ATG8; FLZ; SnRK1; autophagy; carbon starvation
    DOI:  https://doi.org/10.1080/15548627.2023.2247741
  7. Curr Biol. 2023 Aug 04. pii: S0960-9822(23)00977-6. [Epub ahead of print]
    Host nutrient sensing is mediated by mTOR signaling in cnidarian-dinoflagellate symbiosis.
    Philipp A Voss, Sebastian G Gornik, Marie R Jacobovitz, Sebastian Rupp, Melanie Dörr, Ira Maegele, Annika Guse.
      To survive in the nutrient-poor waters of the tropics, reef-building corals rely on intracellular, photosynthetic dinoflagellate symbionts. Photosynthates produced by the symbiont are translocated to the host, and this enables corals to form the structural foundation of the most biodiverse of all marine ecosystems. Although the regulation of nutrient exchange between partners is critical for ecosystem stability and health, the mechanisms governing how nutrients are sensed, transferred, and integrated into host cell processes are largely unknown. Ubiquitous among eukaryotes, the mechanistic target of the rapamycin (mTOR) signaling pathway integrates intracellular and extracellular stimuli to influence cell growth and cell-cycle progression and to balance metabolic processes. A functional role of mTOR in the integration of host and symbiont was demonstrated in various nutritional symbioses, and a similar role of mTOR was proposed for coral-algal symbioses. Using the endosymbiosis model Aiptasia, we examined the role of mTOR signaling in both larvae and adult polyps across various stages of symbiosis. We found that symbiosis enhances cell proliferation, and using an Aiptasia-specific antibody, we localized mTOR to symbiosome membranes. We found that mTOR signaling is activated by symbiosis, while inhibition of mTOR signaling disrupts intracellular niche establishment and symbiosis altogether. Additionally, we observed that dysbiosis was a conserved response to mTOR inhibition in the larvae of a reef-building coral species. Our data confim that mTOR signaling plays a pivotal role in integrating symbiont-derived nutrients into host metabolism and symbiosis stability, ultimately allowing symbiotic cnidarians to thrive in challenging environments.
    DOI:  https://doi.org/10.1016/j.cub.2023.07.038
  8. mSphere. 2023 Aug 15. e0027323
    The RNA-binding protein RBP42 regulates cellular energy metabolism in mammalian-infective Trypanosoma brucei.
    Anish Das, Tong Liu, Hong Li, Seema Husain.
      RNA-binding proteins (RBPs) are key players in coordinated post-transcriptional regulation of functionally related genes, defined as RNA regulons. RNA regulons play particularly critical roles in parasitic trypanosomes, which exhibit unregulated co-transcription of long unrelated gene arrays. In this report, we present a systematic analysis of an essential RBP, RBP42, in the mammalian-infective bloodstream form of African trypanosome and show that RBP42 is a key regulator of parasite's central carbon and energy metabolism. Using individual-nucleotide resolution UV cross-linking and immunoprecipitation to identify genome-wide RBP42-RNA interactions, we show that RBP42 preferentially binds within the coding region of mRNAs encoding core metabolic enzymes. Global quantitative transcriptomic and proteomic analyses reveal that loss of RBP42 reduces the abundance of target mRNA-encoded proteins, but not target mRNA, suggesting a positive translational regulatory role of RBP42. Significant changes in central carbon metabolic intermediates, following loss of RBP42, further support its critical role in cellular energy metabolism. IMPORTANCE Trypanosoma brucei infection, transmitted through the bite of blood-feeding tsetse flies, causes deadly diseases in humans and livestock. This disease, if left untreated, is almost always fatal. Existing therapies are toxic and difficult to administer. During T. brucei's lifecycle in two different host environments, the parasite progresses through distinctive life stages with major morphological and metabolic changes, requiring precise alteration of parasite gene expression program. In the absence of regulated transcription, post-transcriptional processes mediated by RNA-binding proteins play critical roles in T. brucei gene regulation. In this study, we show that the RNA-binding protein RBP42 plays crucial roles in cellular energy metabolic regulation of this important human pathogen. Metabolic dysregulation observed in RBP42 knockdown cells offers a breadth of potential interest to researchers studying parasite biology and can also impact research in general eukaryotic biology.
    Keywords:  RBP42; RNA regulon; RNA-binding protein; Trypanosoma; iCLIP; metabolism; protozoa
    DOI:  https://doi.org/10.1128/msphere.00273-23
  9. J Cell Sci. 2023 Aug 15. pii: jcs259725. [Epub ahead of print]136(16):
    Post-translational modifications of ATG8 proteins - an emerging mechanism of autophagy control.
    Jose L Nieto-Torres, Sviatlana Zaretski, Tianhui Liu, Peter D Adams, Malene Hansen.
      Autophagy is a recycling mechanism involved in cellular homeostasis with key implications for health and disease. The conjugation of the ATG8 family proteins, which includes LC3B (also known as MAP1LC3B), to autophagosome membranes, constitutes a hallmark of the canonical autophagy process. After ATG8 proteins are conjugated to the autophagosome membranes via lipidation, they orchestrate a plethora of protein-protein interactions that support key steps of the autophagy process. These include binding to cargo receptors to allow cargo recruitment, association with proteins implicated in autophagosome transport and autophagosome-lysosome fusion. How these diverse and critical protein-protein interactions are regulated is still not well understood. Recent reports have highlighted crucial roles for post-translational modifications of ATG8 proteins in the regulation of ATG8 functions and the autophagy process. This Review summarizes the main post-translational regulatory events discovered to date to influence the autophagy process, mostly described in mammalian cells, including ubiquitylation, acetylation, lipidation and phosphorylation, as well as their known contributions to the autophagy process, physiology and disease.
    Keywords:  ATG8; Autophagy; GABARAP; LC3; Phosphorylation; Post-translational modifications
    DOI:  https://doi.org/10.1242/jcs.259725
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