Glia-neuron coupling via a bipartite sialylation pathway promotes neural transmission and stress tolerance in Drosophila

  1. Hilary Scott
  2. Boris Novikov
  3. Berrak Ugur
  4. Brooke Allen
  5. Ilya Mertsalov
  6. Pedro Monagas-Valentin
  7. Melissa Koff
  8. Sarah Baas Robinson
  9. Kazuhiro Aoki
  10. Raisa Veizaj
  11. Dirk Lefeber
  12. Michael Tiemeyer
  13. Hugo J Bellen
  14. Vladislav Panin  Is a corresponding author
  1. Texas A&M University, United States
  2. Baylor College of Medicine, United States
  3. University of Georgia, United States
  4. Radboud University Nijmegen Medical Centre, Netherlands

Abstract

Modification by sialylated glycans can affect protein functions, underlying mechanisms that control animal development and physiology. Sialylation relies on a dedicated pathway involving evolutionarily conserved enzymes, including CMP-sialic acid synthetase (CSAS) and sialyltransferase (SiaT) that mediate the activation of sialic acid and its transfer onto glycan termini, respectively. In Drosophila, CSAS and DSiaT genes function in the nervous system, affecting neural transmission and excitability. We found that these genes function in different cells: the function of CSAS is restricted to glia, while DSiaT functions in neurons. This partition of the sialylation pathway allows for regulation of neural functions via a glia-mediated control of neural sialylation. The sialylation genes were shown to be required for tolerance to heat and oxidative stress and for maintenance of the normal level of voltage-gated sodium channels. Our results uncovered a unique bipartite sialylation pathway that mediates glia-neuron coupling and regulates neural excitability and stress tolerance.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been uploaded to a public repository for Tables 1 and Supplementary Table 3

The following data sets were generated

Article and author information

Author details

  1. Hilary Scott

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  2. Boris Novikov

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  3. Berrak Ugur

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4806-8891
  4. Brooke Allen

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  5. Ilya Mertsalov

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  6. Pedro Monagas-Valentin

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  7. Melissa Koff

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    Competing interests
    No competing interests declared.
  8. Sarah Baas Robinson

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
  9. Kazuhiro Aoki

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
  10. Raisa Veizaj

    Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  11. Dirk Lefeber

    Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  12. Michael Tiemeyer

    Complex Carbohydrate Research Center, University of Georgia, Athens, United States
    Competing interests
    No competing interests declared.
  13. Hugo J Bellen

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    Hugo J Bellen, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5992-5989
  14. Vladislav Panin

    Department of Biochemistry and Biophysics, Texas A&M University, College Station, United States
    For correspondence
    panin@tamu.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9126-1481

Funding

National Institutes of Health (NS099409)

  • Vladislav Panin

National Institutes of Health (NS075534)

  • Vladislav Panin

TAMU-COANCYT (2012-037(S))

  • Vladislav Panin

TAMU AgriLife IHA

  • Vladislav Panin

National Institutes of Health (GM103490)

  • Michael Tiemeyer

Radboud Consortium for Glycoscience

  • Dirk Lefeber

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Scott et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,236
    views
  • 212
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Hilary Scott
  2. Boris Novikov
  3. Berrak Ugur
  4. Brooke Allen
  5. Ilya Mertsalov
  6. Pedro Monagas-Valentin
  7. Melissa Koff
  8. Sarah Baas Robinson
  9. Kazuhiro Aoki
  10. Raisa Veizaj
  11. Dirk Lefeber
  12. Michael Tiemeyer
  13. Hugo J Bellen
  14. Vladislav Panin
(2023)
Glia-neuron coupling via a bipartite sialylation pathway promotes neural transmission and stress tolerance in Drosophila
eLife 12:e78280.
https://doi.org/10.7554/eLife.78280

Share this article

https://doi.org/10.7554/eLife.78280

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Santi Mestre-Fos, Lucas Ferguson ... Jamie HD Cate
    Research Article

    Stem cell differentiation involves a global increase in protein synthesis to meet the demands of specialized cell types. However, the molecular mechanisms underlying this translational burst and the involvement of initiation factors remains largely unknown. Here, we investigate the role of eukaryotic initiation factor 3 (eIF3) in early differentiation of human pluripotent stem cell (hPSC)-derived neural progenitor cells (NPCs). Using Quick-irCLIP and alternative polyadenylation (APA) Seq, we show eIF3 crosslinks predominantly with 3’ untranslated region (3’-UTR) termini of multiple mRNA isoforms, adjacent to the poly(A) tail. Furthermore, we find that eIF3 engagement at 3’-UTR ends is dependent on polyadenylation. High eIF3 crosslinking at 3’-UTR termini of mRNAs correlates with high translational activity, as determined by ribosome profiling, but not with translational efficiency. The results presented here show that eIF3 engages with 3’-UTR termini of highly translated mRNAs, likely reflecting a general rather than specific regulatory function of eIF3, and supporting a role of mRNA circularization in the mechanisms governing mRNA translation.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease
    Ana Patrícia Graça, Vadim Nikitushkin ... Gerald Lackner
    Research Article

    Mycofactocin is a redox cofactor essential for the alcohol metabolism of mycobacteria. While the biosynthesis of mycofactocin is well established, the gene mftG, which encodes an oxidoreductase of the glucose-methanol-choline superfamily, remained functionally uncharacterized. Here, we show that MftG enzymes are almost exclusively found in genomes containing mycofactocin biosynthetic genes and are present in 75% of organisms harboring these genes. Gene deletion experiments in Mycolicibacterium smegmatis demonstrated a growth defect of the ∆mftG mutant on ethanol as a carbon source, accompanied by an arrest of cell division reminiscent of mild starvation. Investigation of carbon and cofactor metabolism implied a defect in mycofactocin reoxidation. Cell-free enzyme assays and respirometry using isolated cell membranes indicated that MftG acts as a mycofactocin dehydrogenase shuttling electrons toward the respiratory chain. Transcriptomics studies also indicated remodeling of redox metabolism to compensate for a shortage of redox equivalents. In conclusion, this work closes an important knowledge gap concerning the mycofactocin system and adds a new pathway to the intricate web of redox reactions governing the metabolism of mycobacteria.