Drug resistance–associated mutations in Plasmodium UBP-1 disrupt its essential deubiquitinating activity
Deubiquitinating enzymes function to cleave ubiquitin (Ub) moieties from modified proteins, serving to maintain the pool of free Ub in the cell while simultaneously impacting the fate and function of a target protein. Like all eukaryotes, Plasmodium parasites rely on the dynamic addition and removal of Ub for their own growth and survival. While humans possess around 100 deubiquitinases, Plasmodium contains ∼20 putative Ub hydrolases, many of which bear little to no resemblance to those of other organisms. In this study, we characterize Plasmodium falciparum UBP-1, a large Ub hydrolase unique to Plasmodium spp., which has been linked to endocytosis and drug resistance. We demonstrate its Ub activity, linkage specificity, and assess the repercussions of point mutations associated with drug resistance on catalytic activity and parasite fitness. We confirm that the deubiquitinating activity of UBP-1 is essential for parasite survival, implicating an important role for Ub signaling in endocytosis.
Authors
- Johanna Hoshizaki (ORCID: https://orcid.org/0000-0002-0365-3950)
- Ryan C. Henrici
- Maryia Karpiyevich
- Colin J. Sutherland (ORCID: https://orcid.org/0000-0003-1592-6407)
- Katerina Artavanis‐Tsakonas (ORCID: https://orcid.org/0000-0003-1164-1965)
- Gerbrand J. van der Heden van Noort (ORCID: https://orcid.org/0000-0001-5955-6431)
- Cameron L. C. Smith (ORCID: https://orcid.org/0000-0002-4048-827X)
- Megan R. Ansbro (ORCID: https://orcid.org/0000-0002-7131-1610)
- David B. Ascher (ORCID: https://orcid.org/0000-0003-2948-2413)
- Lee M (ORCID: https://orcid.org/0000-0002-4973-0915)
- C. Stephen Briggs
- Heledd Eavis
Institutions
- The University of Queensland (AU)
- University of Cambridge (GB)
- Leiden University Medical Center (NL)
- Wellcome Sanger Institute (GB)
- London School of Hygiene & Tropical Medicine (GB)
- Wellcome Centre for Anti-Infectives Research (GB)
Publication Details
- Journal
- Journal of Biological Chemistry
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1016/j.jbc.2025.108266
- Citations
- 3
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Wellcome Trust
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- National Health and Medical Research Council