bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2023–11–19
nine papers selected by
Lakesh Kumar, BITS Pilani
  1. Essential role of the conserved oligomeric Golgi complex in Toxoplasma gondii.
  2. SPARK regulates AGC kinases central to the Toxoplasma gondii asexual cycle.
  3. Global Proteome-Wide Analysis of Cysteine S-Nitrosylation in Toxoplasma gondii.
  4. Translation initiation factor eIF1.2 promotes Toxoplasma stage conversion by regulating levels of key differentiation factors.
  5. p97/VCP targets Toxoplasma gondii vacuoles for parasite restriction in interferon-stimulated human cells.
  6. Nuclear Pyruvate Dehydrogenase Complex Regulates Histone Acetylation and Transcriptional Regulation in the Ethylene Response.
  7. In Vitro Virulence Contrast of Seven Genetically Distinct Toxoplasma gondii Isolates After Rejuvenation In Vivo.
  8. HDAC activity is dispensable for repression of cell-cycle genes by DREAM and E2F:RB complexes.
  9. Balancing the interplay of histone deacetylases and non-coding genomes: a step closer to understand the landscape of cancer treatment.
  1. mBio. 2023 Nov 15. e0251323
    Essential role of the conserved oligomeric Golgi complex in Toxoplasma gondii.
    Clem Marsilia, Mrinalini Batra, Irina D Pokrovskaya, Changqi Wang, Dale Chaput, Daria A Naumova, Vladimir V Lupashin, Elena S Suvorova.
       IMPORTANCE: The Golgi is an essential eukaryotic organelle and a major place for protein sorting and glycosylation. Among apicomplexan parasites, Toxoplasma gondii retains the most developed Golgi structure and produces many glycosylated factors necessary for parasite survival. Despite its importance, Golgi function received little attention in the past. In the current study, we identified and characterized the conserved oligomeric Golgi complex and its novel partners critical for protein transport in T. gondii tachyzoites. Our results suggest that T. gondii broadened the role of the conserved elements and reinvented the missing components of the trafficking machinery to accommodate the specific needs of the opportunistic parasite T. gondii.
    Keywords:  AP-5; COPI; COPII; Golgi; Toxoplasma gondii; anterograde transport; apicomplexa; glycosylation; retrograde transport; vesicular transport
    DOI:  https://doi.org/10.1128/mbio.02513-23
  2. bioRxiv. 2023 Oct 30. pii: 2023.10.30.564746. [Epub ahead of print]
    SPARK regulates AGC kinases central to the Toxoplasma gondii asexual cycle.
    Alice L Herneisen, Michelle L Peters, Tyler A Smith, Sebastian Lourido.
      Apicomplexan parasites balance proliferation, persistence, and spread in their metazoan hosts. AGC kinases, such as PKG, PKA, and the PDK1 ortholog SPARK, integrate environmental signals to toggle parasites between replicative and motile life stages. Recent studies have cataloged pathways downstream of apicomplexan PKG and PKA; however, less is known about the global integration of AGC kinase signaling cascades. Here, conditional genetics coupled to unbiased proteomics demonstrates that SPARK complexes with an elongin-like protein to regulate the stability of PKA and PKG in the model apicomplexan Toxoplasma gondii . Defects attributed to SPARK depletion develop after PKG and PKA are down-regulated. Parasites lacking SPARK differentiate into the chronic form of infection, which may arise from reduced activity of a coccidian-specific PKA ortholog. This work delineates the signaling topology of AGC kinases that together control transitions within the asexual cycle of this important family of parasites.
    DOI:  https://doi.org/10.1101/2023.10.30.564746
  3. Molecules. 2023 Oct 29. pii: 7329. [Epub ahead of print]28(21):
    Global Proteome-Wide Analysis of Cysteine S-Nitrosylation in Toxoplasma gondii.
    Zexiang Wang, Jia Li, Qianqian Yang, Xiaolin Sun.
      Toxoplasma gondii transmits through various routes, rapidly proliferates during acute infection and causes toxoplasmosis, which is an important zoonotic disease in human and veterinary medicine. T. gondii can produce nitric oxide and derivatives, and S-nitrosylation contributes to their signaling transduction and post-translation regulation. To date, the S-nitrosylation proteome of T. gondii remains mystery. In this study, we reported the first S-nitrosylated proteome of T. gondii using mass spectrometry in combination with resin-assisted enrichment. We found that 637 proteins were S-nitrosylated, more than half of which were localized in the nucleus or cytoplasm. Motif analysis identified seven motifs. Of these motifs, five and two contained lysine and isoleucine, respectively. Gene Ontology enrichment revealed that S-nitrosylated proteins were primarily located in the inner membrane of mitochondria and other organelles. These S-nitrosylated proteins participated in diverse biological and metabolic processes, including organic acid binding, carboxylic acid binding ribose and phosphate biosynthesis. T. gondii S-nitrosylated proteins significantly contributed to glycolysis/gluconeogenesis and aminoacyl-tRNA biosynthesis. Moreover, 27 ribosomal proteins and 11 microneme proteins were identified as S-nitrosylated proteins, suggesting that proteins in the ribosome and microneme were predominantly S-nitrosylated. Protein-protein interaction analysis identified three subnetworks with high-relevancy ribosome, RNA transport and chaperonin complex components. These results imply that S-nitrosylated proteins of T. gondii are associated with protein translation in the ribosome, gene transcription, invasion and proliferation of T. gondii. Our research is the first to identify the S-nitrosylated proteomic profile of T. gondii and will provide direction to the ongoing investigation of the functions of S-nitrosylated proteins in T. gondii.
    Keywords:  S-nitrosylated proteome; Toxoplasma gondii; cysteine S-nitrosylation; post-translational modification
    DOI:  https://doi.org/10.3390/molecules28217329
  4. bioRxiv. 2023 Nov 03. pii: 2023.11.03.565545. [Epub ahead of print]
    Translation initiation factor eIF1.2 promotes Toxoplasma stage conversion by regulating levels of key differentiation factors.
    Fengrong Wang, Michael J Holmes, Hea Jin Hong, Pariyamon Thaprawat, Geetha Kannan, My-Hang Huynh, Tracey L Schultz, M Haley Licon, Sebastian Lourido, William J Sullivan, Seán E O'Leary, Vern B Carruthers.
      The parasite Toxoplasma gondii persists in its hosts by converting from replicating tachyzoites to latent bradyzoites housed in tissue cysts. The molecular mechanisms that mediate T. gondii differentiation remain poorly understood. Through a mutagenesis screen, we identified translation initiation factor eIF1.2 as a critical factor for T. gondii differentiation. A F97L mutation in eIF1.2 or the genetic ablation of eIF1.2 (Δ eIF1.2 ) markedly impeded bradyzoite cyst formation in vitro and in vivo . We demonstrated, at single-molecule level, that the eIF1.2 F97L mutation impacts the scanning process of the ribosome preinitiation complex on a model mRNA. RNA sequencing and ribosome profiling experiments unveiled that Δ eIF1.2 parasites are defective in the upregulating bradyzoite induction factors BFD1 and BFD2 during stress-induced differentiation. Forced expression of BFD1 or BFD2 significantly restored differentiation in Δ eIF1.2 parasites. Together, our findings suggest that eIF1.2 functions by regulating the translation of key differentiation factors necessary to establish chronic toxoplasmosis.
    DOI:  https://doi.org/10.1101/2023.11.03.565545
  5. mSphere. 2023 Nov 17. e0051123
    p97/VCP targets Toxoplasma gondii vacuoles for parasite restriction in interferon-stimulated human cells.
    Barbara Clough, Daniel Fisch, Todd H Mize, Vesela Encheva, Ambrosius Snijders, Eva-Maria Frickel.
       IMPORTANCE: Toxoplasma gondii (Tg) is a ubiquitous parasitic pathogen, infecting about one-third of the global population. Tg is controlled in immunocompetent people by mechanisms that are not fully understood. Tg infection drives the production of the inflammatory cytokine interferon gamma (IFNγ), which upregulates intracellular anti-pathogen defense pathways. In this study, we describe host proteins p97/VCP, UBXD1, and ANKRD13A that control Tg at the parasitophorous vacuole (PV) in IFNγ-stimulated endothelial cells. p97/VCP is an ATPase that interacts with a network of cofactors and is active in a wide range of ubiquitin-dependent cellular processes. We demonstrate that PV ubiquitination is a pre-requisite for recruitment of these host defense proteins, and their deposition directs Tg PVs to acidification in endothelial cells. We show that p97/VCP universally targets PVs in human cells and restricts Tg in different human cell types. Overall, these findings reveal new players of intracellular host defense of a vacuolated pathogen.
    Keywords:  ANKRD13A; Toxoplasma gondii; UBXD1; innate immunity; p97/VCP; parasitophorous vacuole; ubiquitin
    DOI:  https://doi.org/10.1128/msphere.00511-23
  6. bioRxiv. 2023 Oct 27. pii: 2023.10.25.564010. [Epub ahead of print]
    Nuclear Pyruvate Dehydrogenase Complex Regulates Histone Acetylation and Transcriptional Regulation in the Ethylene Response.
    Zhengyao Shao, Liangqiao Bian, Shyon K Ahmadi, Tyler J Daniel, Miguel A Belmonte, Jackson G Burns, Prashanth Kotla, Yang Bi, Zhouxin Shen, Shou-Ling Xu, Zhi-Yong Wang, Steven P Briggs, Hong Qiao.
      Ethylene plays its essential roles in plant development, growth, and defense responses by controlling the transcriptional reprograming, in which EIN2-C-directed regulation of histone acetylation is the first key-step for chromatin to perceive ethylene signaling. But how the nuclear acetyl coenzyme A (acetyl CoA) is produced to ensure the ethylene-mediated histone acetylation is unknown. Here we report that ethylene triggers the accumulation of the pyruvate dehydrogenase complex (PDC) in the nucleus to synthesize nuclear acetyl CoA to regulate ethylene response. PDC is identified as an EIN2-C nuclear partner, and ethylene triggers its nuclear accumulation. Mutations in PDC lead to an ethylene-hyposensitivity that results from the reduction of histone acetylation and transcription activation. Enzymatically active nuclear PDC synthesize nuclear acetyl CoA for EIN2-C-directed histone acetylation and transcription regulation. These findings uncover a mechanism by which PDC-EIN2 converges the mitochondrial enzyme mediated nuclear acetyl CoA synthesis with epigenetic and transcriptional regulation for plant hormone response.
    DOI:  https://doi.org/10.1101/2023.10.25.564010
  7. Acta Parasitol. 2023 Nov 18.
    In Vitro Virulence Contrast of Seven Genetically Distinct Toxoplasma gondii Isolates After Rejuvenation In Vivo.
    Haiting Guo, Jie Tan, Yulin He, Shumin Yuan, Ke Jin, Zhongyuan Li.
       BACKGROUND: In the past for more than 100 years at least 300 genotypes of Toxoplasma gondii were recorded and several traditional isolates such as RH, GT1, ME49, PRU and VEG were used repeatedly to clarify the pathogenic mechanisms and the epidemiological significance to human, but for if their virulence was mutative post-iterative passages it remains confused.
    OBJECTIVE: Therefore, in the study, seven genetically distinct T. gondii including C7 and PYS previously discovered in China were reidentified by sequencing the head of hsp40 locus to distinguish their virulence in vitro post-rejuvenation in vivo.
    RESULTS: Our data showed the nucleotides were different in 18 positions and 7 of them can be used to type T. gondii isolates. Total 634 plaques of T. gondii without two or more overlaps indicated that RH and GT1 tachyzoites possess stronger power than other five isolates in vitro (p < 0.001), followed by ME49, PRU, C7, PYS, and the weakest VEG. Based on the shapes of plaques, we found the ratio of their width/length was associated with the virulence of T. gondii, and speculated it could be used to judge T. gondii tachyzoites in vitro, whereas the data of simple linear regression analyses did not agree.
    CONCLUSIONS: Together, virulence of seven genetically distinct T. gondii isolates that can be distinguished by seven mutative nucleotides in hsp40 was redefined in vitro post-rejuvenation in vivo, and it cannot be directly judged just according to the shapes of plaques formed in vitro.
    Keywords:  HFF monolayer; Linear regression; Rejuvenation; Toxoplasma gondii; Virulence; hsp40
    DOI:  https://doi.org/10.1007/s11686-023-00740-8
  8. bioRxiv. 2023 Oct 28. pii: 2023.10.28.564489. [Epub ahead of print]
    HDAC activity is dispensable for repression of cell-cycle genes by DREAM and E2F:RB complexes.
    Alison Barrett, Manisha R Shingare, Andreas Rechtsteiner, Tilini U Wijeratne, Kelsie M Rodriguez, Seth M Rubin, Gerd A Müller.
      Histone deacetylases (HDACs) are pivotal in transcriptional regulation, and their dysregulation has been associated with various diseases including cancer. One of the critical roles of HDAC-containing complexes is the deacetylation of histone tails, which is canonically linked to transcriptional repression. Previous research has indicated that HDACs are recruited to cell-cycle gene promoters through the RB protein or the DREAM complex via SIN3B and that HDAC activity is essential for repressing G1/S and G2/M cell-cycle genes during cell-cycle arrest and exit. In this study, we sought to explore the interdependence of DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression. We found that genetic knockout of SIN3B did not lead to derepression of cell-cycle genes in non-proliferating HCT116 and C2C12 cells. A combined loss of SIN3A and SIN3B resulted in a moderate upregulation in mRNA expression of several cell-cycle genes in arrested HCT116 cells, however, these effects appeared to be independent of DREAM or RB. Furthermore, HDAC inhibition did not induce a general upregulation of RB and DREAM target gene expression in arrested transformed or non-transformed cells. Our findings provide evidence that E2F:RB and DREAM complexes can repress cell-cycle genes without reliance on HDAC activity.
    DOI:  https://doi.org/10.1101/2023.10.28.564489
  9. BMC Med Genomics. 2023 Nov 17. 16(1): 295
    Balancing the interplay of histone deacetylases and non-coding genomes: a step closer to understand the landscape of cancer treatment.
    Jingjing Pu, Ting Liu, Amit Sharma, Ingo G H Schmidt-Wolf.
      Histone deacetylase (HDAC) inhibitors have enormous therapeutic potential as effective epigenetic regulators, and now with the focus on the selective HDAC6 inhibitor in ongoing clinical trials, more advantages over other non-selective pan-HDAC inhibitors are foreseeable. As it is of paramount importance to understand the complex regulatory web of mutual interactions involving epigenetic machinery and non-coding genome in regulating gene expression, herein, we investigated the intriguing interactions between HDAC6-induced lncRNA (LINC00152) and its possible sponge miRNA (hsa-miR-499a-5p) in multiple myeloma.
    Keywords:  Cancer; Epigenetics; Histone deacetylases; Non-coding genome
    DOI:  https://doi.org/10.1186/s12920-023-01724-3
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