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PreprintCited by 7Trypanosoma species research and implicationsAdvanced Proteomics Techniques and ApplicationsResearch on Leishmaniasis Studies

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High confidence glycosomal membrane protein inventory unveils trypanosomal Peroxin PEX15

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Krishna, Chethan K., Das, Hirak, Hohnen, Lisa, Schliebs, Wolfgang, Oeljeklaus, Silke, Warscheid, Bettina, Kalel, Vishal C., Erdmann, Ralf·2023·Cell Reports
DOI 10.1101/2023.10.13.562043

Preprint — published as 10.1016/j.celrep.2025.115614 · Paper page

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Abstract

Infections by trypanosomatid parasites cause Chagas disease, Human African Trypanosomiasis, and Leishmaniasis, affecting over 12 million people worldwide. Glycosomes, the unique peroxisome-related organelles of trypanosomes are essential for their survival, and hence their metabolic functions and biogenesis mediated by peroxins (PEX) are suitable as drug targets. Here we report on a comprehensive protein inventory of glycosomal membranes through advanced subcellular membrane protein profiling employing quantitative mass spectrometry. Our quantitative analysis resulted in the identification of 28 novel high confidence glycosomal membrane proteins. Our in-depth protein inventory of glycosomal membranes serves as an important resource for characterizing glycosome biology and drug development. We validated four so far unknown glycosomal membrane proteins, including two tail-anchored (TA) proteins, a homolog of human peroxisomal PXMP4, and a Macrodomain-containing protein. Using a structure-based approach, we identified one of the TA proteins as the long-sought Trypanosoma PEX15. Despite its low sequence similarity, Trypanosoma PEX15 exhibits structural and topological similarities with its yeast (Pex15) and human counterparts (PEX26). We show that PEX15 is an essential integral glycosomal membrane protein that interacts with PEX6. Accordingly, RNAi knockdown of PEX15 in bloodstream form trypanosomes demonstrates that it is essential for glycosome biogenesis and parasite survival. Considering the low degree of conservation with its human counterpart, PEX15 is a promising molecular target for drug development.

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Metadata

Authors
Krishna, C. K., Das, H., Hohnen, L., Schliebs, W., Oeljeklaus, S., Warscheid, B., Kalel, V. C., & Erdmann, R.
Affiliations
  • Ruhr University Bochum (DE)
  • University of Würzburg (DE)
ORCID
Venue
Cell Reports
Publisher
openRxiv
Published
2023-10-14
Volume
44
Issue
5
Pages
115614-115614
ISSN
2211-1247 (ISSN-L)
DOI
10.1101/2023.10.13.562043
OpenAlex
W4409745703
Cited by
7
References
1
Citations by year
2026: 3 · 2025: 3 · 2024: 1
FWCI
4.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • European Commission (812968, HORIZON2020)
  • Deutsche Forschungsgemeinschaft (SPP2453, 541758684, ER178/17-1, FOR1905, GRK 2234/2)
  • National Institutes of Health
  • University of California, San Francisco (P41-GM103311)
  • Horizon 2020 Framework Programme
  • Horizon 2020
  • National Institute of General Medical Sciences (P41GM103311)
  • H2020 Marie Skłodowska-Curie Actions
  • FP7 People: Marie-Curie Actions (812968)
Topics
  • Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
Keywords
glycosomes, peroxisome biogenesis, peroxins, trypanosomes, tail-anchored proteins, Chagas disease, leishmaniasis, sleeping sickness
MeSH terms
Peroxins, Amino Acid Sequence, Humans, Membrane Proteins, Microbodies, Trypanosoma, Trypanosoma brucei brucei, Protozoan Proteins

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