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Cited by 5Trypanosoma species research and implicationsRNA Research and SplicingResearch on Leishmaniasis Studies

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Differentiation granules, a dynamic regulator of T. brucei development

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Cayla, Mathieu, Spanos, Christos, McWilliam, Kirsty, Waskett, Eliza, Rappsilber, Juri, Matthews, Keith R.·2024·Nature Communications
DOI 10.1038/s41467-024-47309-1PMC PMC10998879

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Abstract

Adaptation to a change of environment is an essential process for survival, in particular for parasitic organisms exposed to a wide range of hosts. Such adaptations include rapid control of gene expression through the formation of membraneless organelles composed of poly-A RNA and proteins. The African trypanosome Trypanosoma brucei is exquisitely sensitive to well-defined environmental stimuli that trigger cellular adaptations through differentiation events that characterise its complex life cycle. The parasite has been shown to form stress granules in vitro, and it has been proposed that such a stress response could have been repurposed to enable differentiation and facilitate parasite transmission. Therefore, we explored the composition and positional dynamics of membraneless granules formed in response to starvation stress and during differentiation in the mammalian host between the replicative slender and transmission-adapted stumpy forms. We find that T. brucei differentiation does not reflect the default response to environmental stress. Instead, the developmental response of the parasites involves a specific and programmed hierarchy of membraneless granule assembly, with distinct components and regulation by protein kinases such as TbDYRK, that are required for the parasite to successfully progress through its life cycle development and prepare for transmission.

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  1. Kolev, N. G., Ramey-Butler, K., Cross, G. A. M., Ullu, E. & Tschudi, C. Developmental progression to infectivity in Trypanosoma brucei triggered by an RNA-binding protein. Science 338, 1352–1353 (2012). · DOI
  2. Shi, H., Butler, K. & Tschudi, C. A single-point mutation in the RNA-binding protein 6 generates Trypanosoma brucei metacyclics that are able to progress to bloodstream forms in vitro. Mol. Biochem. Parasitol. 224, 50–56 (2018). · DOI
  3. Perez-Pepe, M., Fernández-Alvarez, A. J. & Boccaccio, G. L. Life and work of stress granules and processing bodies: new insights into their formation and function. Biochemistry 57, 2488–2498 (2018). · DOI
  4. Kedersha, N. & Anderson, P. Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. in Biochemical Society Transactions Vol. 30, 963–969 (Portland Press, 2002). · DOI
  5. Saad, S. et al. Reversible protein aggregation is a protective mechanism to ensure cell cycle restart after stress. Nat. Cell Biol. 19, 1202–1213 (2017). · DOI
  6. Ivanov, P., Kedersha, N. & Anderson, P. Stress granules and processing bodies in translational control. Cold Spring Harb. Perspect. Biol. 11, a032813 (2019). · DOI
  7. Moon, S. L., Morisaki, T., Stasevich, T. J. & Parker, R. Coupling of translation quality control and mRNA targeting to stress granules. J. Cell Biol. 219, e202004120 (2020). · DOI
  8. Anadolu, M. N. et al. Ribosomes in RNA granules are stalled on mRNA sequences that are consensus sites of FMRP association. J. Neurosci. 43, 2440–2459 (2023). · DOI
  9. Wippich, F. et al. Dual specificity kinase DYRK3 couples stress granule condensation/ dissolution to mTORC1 signaling. Cell 152, 791–805 (2013). · DOI
  10. Rai, A. K., Chen, J.-X. X., Selbach, M. & Pelkmans, L. Kinase-controlled phase transition of membraneless organelles in mitosis. Nature 559, 211–216 (2018). · DOI
  11. Hofweber, M. & Dormann, D. Friend or foe—post-translational modifications as regulators of phase separation and RNP granule dynamics. J. Biol. Chem. 294, 7137–7150 (2019). · DOI
  12. Mediani, L. et al. Hsp90-mediated regulation of DYRK3 couples stress granule disassembly and growth via mTORC1 signaling. EMBO Rep. 22, e51740 (2021). · DOI
  13. Cassola, A., De Gaudenzi, J. G. & Frasch, A. C. Recruitment of mRNAs to cytoplasmic ribonucleoprotein granules in trypanosomes. Mol. Microbiol. 65, 655–670 (2007). · DOI
  14. Mani, J. et al. Alba-domain proteins of Trypanosoma brucei are cytoplasmic RNA-Binding proteins that interact with the translation machinery. PLoS One 6, e22463 (2011). · DOI
  15. Subota, I. et al. ALBA proteins are stage regulated during trypanosome development in the tsetse fly and participate in differentiation. Mol. Biol. Cell 22, 4205–4219 (2011). · DOI
  16. Fritz, M. et al. Novel insights into RNP granules by employing the trypanosome’s microtubule skeleton as a molecular sieve. Nucleic Acids Res. 43, 8013–8032 (2015). · DOI
  17. Kafková, L. et al. Trypanosoma brucei PRMT1 is a nucleic acid binding protein with a role in energy metabolism and the starvation stress response. mBio 9, 1–19 (2018). · DOI
  18. Malvezzi, A. M. et al. GCN2-like kinase modulates stress granule formation during nutritional stress in trypanosoma cruzi. Front. Cell. Infect. Microbiol. 10, 149 (2020). · DOI
  19. Kramer, S. et al. A unique mRNA decapping complex in trypanosomes. Nucleic Acids Res. gkad497. https://doi.org/10.1093/nar/gkad497 (2023). · DOI
  20. Quintana, J. F., Zoltner, M. & Field, M. C. Evolving differentiation in African trypanosomes. Trends Parasitol. 37, 296–303 (2021). · DOI
  21. Turner, C. M. R., Barry, J. D. & Vickerman, K. Loss of variable antigen during transformation of Trypanosoma brucei rhodesiense from bloodstream to procyclic forms in the tsetse fly. Parasitol. Res. 74, 507–511 (1988). · DOI
  22. Vickerman, K. Polymorphism and mitochondrial activity in sleeping sickness trypanosomes. Nature 208, 762–766 (1965). · DOI
  23. Macleod, O. J. S. et al. A receptor for the complement regulator factor H increases transmission of trypanosomes to tsetse flies. Nat. Commun. 1–46 https://doi.org/10.1038/s41467-020-15125-y (2020). · DOI
  24. Dewar, C. E. et al. Mitochondrial DNA is critical for longevity and metabolism of transmission stage Trypanosoma brucei. PLOS Pathog. 14, e1007195 (2018). · DOI
  25. Matthews, K. R. & Larcombe, S. Comment on ‘Unexpected plasticity in the life cycle of Trypanosoma brucei’. eLife 11, e74985 (2022). · DOI
  26. Ngoune, J. M. T., Sharma, P., Crouzols, A. & Rotureau, B. Stumpy forms are the predominant transmissible forms of Trypanosoma brucei. 2023.08.30.555461 Preprint at https://doi.org/10.1101/2023.08.30.555461 (2023). · DOI
  27. Mony, B. M. et al. Genome-wide dissection of the quorum sensing signalling pathway in Trypanosoma brucei. Nature 505, 681–685 (2014). · DOI
  28. Cayla, M., McDonald, L., MacGregor, P. & Matthews, K. An atypical DYRK kinase connects quorum-sensing with posttranscriptional gene regulation in Trypanosoma brucei. eLife 9, 1–33 (2020). · DOI
  29. McDonald, L. et al. Non-linear hierarchy of the quorum sensing signalling pathway in bloodstream form African trypanosomes. PLoS Pathog. 14, e1007145 (2018). · DOI
  30. Szöőr, B. et al. Positional dynamics and glycosomal recruitment of developmental regulators during trypanosome differentiation. mBio 10, e00875–19 (2019). · DOI
  31. Lam, S. S. et al. Directed evolution of APEX2 for electron microscopy and proximity labeling. Nat. Methods 12, 51–54 (2014). · DOI
  32. Markmiller, S. et al. Context-dependent and disease-specific diversity in protein interactions within stress granules. Cell 172, 590–604.e13 (2018). · DOI
  33. Vélez-Ramírez, D. E. et al. APEX2 proximity proteomics resolves flagellum subdomains and identifies flagellum tip-specific proteins in Trypanosoma brucei. mSphere 6, 1–19 (2021). · DOI
  34. Proto, W. R. et al. Trypanosoma brucei metacaspase 4 is a pseudopeptidase and a virulence factor. J. Biol. Chem. 286, 39914–39925 (2011). · DOI
  35. Creek, D. J. et al. Metabolomics guides rational development of a simplified cell culture medium for drug screening against Trypanosoma brucei. Antimicrob. Agents Chemother. 57, 2768–2779 (2013). · DOI
  36. Moloney, N. M. et al. Mapping diversity in African trypanosomes using high resolution spatial proteomics. Nat. Commun. 14, 4401 (2023). · DOI
  37. Cayla, M., Matthews, K. R. & Ivens, A. C. A global analysis of low-complexity regions in the Trypanosoma brucei proteome reveals enrichment in the C-terminus of nucleic acid binding proteins providing potential targets of phosphorylation. Wellcome Open Res 5, 219 (2020). · DOI
  38. Bevkal, S. et al. An Alba-domain protein required for proteome remodelling during trypanosome differentiation and host transition. PLoS Pathog. 17, 1–30 (2021). · DOI
  39. Stitzel, M. L., Pellettieri, J. & Seydoux, G. The C. elegans DYRK kinase MBK-2 marks oocyte proteins for degradation in response to meiotic maturation. Curr. Biol. 16, 56–62 (2006). · DOI
  40. Alvarez, M., Estivill, X. & de la Luna, S. DYRK1A accumulates in splicing speckles through a novel targeting signal and induces speckle disassembly. J. Cell Sci. 116, 3099–3107 (2003). · DOI
  41. Lee, C.-Y. S. et al. Recruitment of mRNAs to P granules by condensation with intrinsically-disordered proteins. eLife 9, e52896 (2020). · DOI
  42. Updike, D. L., Knutson, A. K., Egelhofer, T. A., Campbell, A. C. & Strome, S. Germ-granule components prevent somatic development in the C. elegans germline. Curr. Biol. CB 24, 970–975 (2014). · DOI
  43. Knutson, A. K., Egelhofer, T., Rechtsteiner, A. & Strome, S. Germ granules prevent accumulation of somatic transcripts in the adult caenorhabditis elegans germline. Genetics 206, 163–178 (2017). · DOI
  44. Dodson, A. E. & Kennedy, S. Phase separation in germ cells and development. Dev. Cell 55, 4–17 (2020). · DOI
  45. Quiroz, F. G. et al. Liquid-liquid phase separation drives skin barrier formation. Science 367, eaax9554 (2020). · DOI
  46. Jeong, S.-G., Ohn, T., Jang, C. H., Vijayakumar, K. & Cho, G.-W. The role of stress granules in the neuronal differentiation of stem cells. Mol. Cells 43, 848–855 (2020).
  47. LANHAM, S. M. Separation of trypanosomes from the blood of infected rats and mice by anion-exchangers. Nature 218, 1273–1274 (1968). · DOI
  48. MacGregor, P., Rojas, F., Dean, S. & Matthews, K. R. Stable transformation of pleomorphic bloodstream form Trypanosoma brucei. Mol. Biochem. Parasitol. 190, 60–62 (2013). · DOI
  49. Beneke, T. et al. A CRISPR Cas9 high-throughput genome editing toolkit for kinetoplastids. R. Soc. Open Sci. 4, 170095 (2017). · DOI
  50. Paterou, A. et al. Unlocking Trypanosome Biology: A Comprehensive Protein-Tagging Toolkit for Localization and Functional Analysis. 2023.04.21.537815 Preprint at https://doi.org/10.1101/2023.04.21.537815 (2023). · DOI
  51. Dean, S., Marchetti, R., Kirk, K. & Matthews, K. R. A surface transporter family conveys the trypanosome differentiation signal. Nature 459, 213–217 (2009). · DOI
  52. Bastin, P., Bagherzadeh, A., Matthews, K. R. & Gull, K. A novel epitope tag system to study protein targeting and organelle biogenesis in Trypanosoma brucei. Mol. Biochem. Parasitol. 77, 235–239 (1996). · DOI
  53. Edelstein, A. D. et al. Advanced methods of microscope control using μManager software.J. Biol. Methods 1, e10 (2014). · DOI
  54. Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012). · DOI · Paper page
  55. Lamour, N. et al. Proline metabolism in procyclic Trypanosoma brucei is. -regulated presence glucose.J. Biol. Chem. 280, 11902–11910 (2005). · DOI
  56. Haanstra, J. R. et al. Proliferating bloodstream-form Trypanosoma brucei use a negligible part of consumed glucose for anabolic processes | Elsevier Enhanced Reader. Int. J. Parasitol. 42, 667–673 (2012). · DOI
  57. OPPERDOES, F. R. et al. Purification, morphometric analysis, and characterization of the glycosomes (microbodies) of the protozoan hemoflagellate Trypanosoma brucei. J. Cell Biol. 98, 1178–1184 (1984). · DOI
  58. Olsen, J. V. et al. Higher-energy C-trap dissociation for peptide modification analysis. Nat. Methods 4, 709–712 (2007). · DOI
  59. Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008). · DOI · Paper page
  60. Cox, J. et al. Andromeda: a peptide search engine integrated into the MaxQuant environment. J. Proteome Res. 10, 1794–1805 (2011). · DOI
  61. Cox, J. et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol. Cell. Proteom. 13, 2513–2526 (2014). · DOI · Paper page
  62. Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543–D552 (2022). · DOI · Paper page
  63. Zhang, X. et al. Proteome-wide identification of ubiquitin interactions using UbIA-MS. Nat. Protoc. 13, 530–550 (2018). · DOI
  64. Aslett, M. et al. TriTrypDB: A functional genomic resource for the Trypanosomatidae. Nucleic Acids Res. 38, 457–462 (2009). · DOI
  65. McWilliam, K. R., Ivens, A., Morrison, L. J., Mugnier, M. R. & Matthews, K. R. Developmental competence and antigen switch frequency can be uncoupled in Trypanosoma brucei. Proc. Natl Acad. Sci. USA 116, 22774–22782 (2019). · DOI
  66. Gale, M., Carter, V. & Parsons, M. Translational control mediates the developmental regulation of the Trypanosoma brucei Nrk protein kinase. J. Biol. Chem. 269, 31659–31665 (1994). · DOI
  67. Jones, N. G. et al. Regulators of Trypanosoma brucei Cell Cycle progression and differentiation identified using a kinome-wide RNAi screen. PLoS Pathog. 10, e1003886 (2014). · DOI
  68. Dejung, M. et al. Quantitative proteomics uncovers novel factors involved in developmental differentiation of Trypanosoma brucei. PLoS Pathog. 12, e1005439 (2016). · DOI
  69. Briggs, E. M., Rojas, F., McCulloch, R., Matthews, K. R. & Otto, T. D. Single-cell transcriptomic analysis of bloodstream Trypanosoma brucei reconstructs cell cycle progression and developmental quorum sensing. Nat. Commun. 12, 5268 (2021). · DOI

Metadata

Authors
Cayla, M., Spanos, C., McWilliam, K., Waskett, E., Rappsilber, J., & Matthews, K. R.
Affiliations
  • University of York (GB)
  • Wellcome Centre for Cell Biology (GB)
  • University of Edinburgh (GB)
Corresponding author
Cayla, Mathieu
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-04-06
Volume
15
Issue
1
Pages
2972-2972
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-47309-1
PMC
PMC10998879
OpenAlex
W4394011034
Cited by
5
References
1
Citations by year
2026: 3 · 2025: 1 · 2024: 1
FWCI
1.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • RCUK | Medical Research Council (MR/W026996/1)
  • Wellcome Trust (108504, 103740/Z14/Z)
  • Wolfson Foundation (WM140045)
Topics
  • Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
Keywords
Trypanosoma brucei, stress granules, biomolecular condensates, polyadenylated RNA, parasite differentiation, life cycle development, gene expression regulation
MeSH terms
Animals, Mammals, Trypanosoma, Trypanosoma brucei brucei

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