Drug resistance–associated mutations in Plasmodium UBP-1 disrupt its essential deubiquitinating activity

Cameron J. Smith; Heledd Eavis; Carla Briggs; Ryan Henrici; Maryia Karpiyevich; Megan R. Ansbro; Johanna Hoshizaki; Gerbrand J. van der Heden van Noort; David B. Ascher; Colin J. Sutherland; Marcus C.S. Lee; Katerina Artavanis-Tsakonas

doi:10.1016/j.jbc.2025.108266

Drug resistance–associated mutations in Plasmodium UBP-1 disrupt its essential deubiquitinating activity

Cameron J. Smith, Heledd Eavis, Carla Briggs, Ryan Henrici, Maryia Karpiyevich, Megan R. Ansbro, Johanna Hoshizaki, Gerbrand J. van der Heden van Noort, David B. Ascher, Colin J. Sutherland, Marcus C.S. Lee, Katerina Artavanis-Tsakonas (Lead / Corresponding author)

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Abstract

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.

Original language	English
Article number	108266
Number of pages	11
Journal	Journal of Biological Chemistry
Volume	301
Issue number	3
Early online date	3 Feb 2025
DOIs	https://doi.org/10.1016/j.jbc.2025.108266
Publication status	Published - 5 Mar 2025

Keywords

DUB
parasite
Plasmodium
ubiquitin
ubiquitin hydrolase

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.jbc.2025.108266Licence: CC BY

1-s2.0-S0021925825001139-main
© 2025 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CCBY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 2.03 MBLicence: CC BY

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Smith, C. J., Eavis, H., Briggs, C., Henrici, R., Karpiyevich, M., Ansbro, M. R., Hoshizaki, J., van der Heden van Noort, G. J., Ascher, D. B., Sutherland, C. J., Lee, M. C. S., & Artavanis-Tsakonas, K. (2025). Drug resistance–associated mutations in Plasmodium UBP-1 disrupt its essential deubiquitinating activity. Journal of Biological Chemistry, 301(3), Article 108266. https://doi.org/10.1016/j.jbc.2025.108266

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abstract = "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.",

keywords = "DUB, parasite, Plasmodium, ubiquitin, ubiquitin hydrolase",

author = "Smith, \{Cameron J.\} and Heledd Eavis and Carla Briggs and Ryan Henrici and Maryia Karpiyevich and Ansbro, \{Megan R.\} and Johanna Hoshizaki and \{van der Heden van Noort\}, \{Gerbrand J.\} and Ascher, \{David B.\} and Sutherland, \{Colin J.\} and Lee, \{Marcus C.S.\} and Katerina Artavanis-Tsakonas",

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doi = "10.1016/j.jbc.2025.108266",

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Smith, CJ, Eavis, H, Briggs, C, Henrici, R, Karpiyevich, M, Ansbro, MR, Hoshizaki, J, van der Heden van Noort, GJ, Ascher, DB, Sutherland, CJ, Lee, MCS & Artavanis-Tsakonas, K 2025, 'Drug resistance–associated mutations in Plasmodium UBP-1 disrupt its essential deubiquitinating activity', Journal of Biological Chemistry, vol. 301, no. 3, 108266. https://doi.org/10.1016/j.jbc.2025.108266

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AU - Smith, Cameron J.

AU - Eavis, Heledd

AU - Briggs, Carla

AU - Henrici, Ryan

AU - Karpiyevich, Maryia

AU - Ansbro, Megan R.

AU - Hoshizaki, Johanna

AU - van der Heden van Noort, Gerbrand J.

AU - Ascher, David B.

AU - Sutherland, Colin J.

AU - Lee, Marcus C.S.

AU - Artavanis-Tsakonas, Katerina

PY - 2025/3/5

Y1 - 2025/3/5

N2 - 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.

AB - 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.

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Drug resistance–associated mutations in Plasmodium UBP-1 disrupt its essential deubiquitinating activity

Abstract

Keywords

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