Leiden University Scholarly Publications

Smith, C.J.; Eavis, H.; Briggs, C.; Henrici, R.; Karpiyevich, M.; Ansbro, M.R.; ... ; Artavanis-Tsakonas, K. (2025)

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

Article / Letter to editor

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 X20 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...Show moreDeubiquitinating 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 X20 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.Show less

All authors

Smith, C.J.; Eavis, H.; Briggs, C.; Henrici, R.; Karpiyevich, M.; Ansbro, M.R.; Hoshizaki, J.; Noort, G.J.V. van; Ascher, D.B.; Sutherland, C.J.; Lee, M.C.S.; Artavanis-Tsakonas, K.

Date

2025-03-05

Journal

Journal of Biological Chemistry

Volume

301

Issue

3

DOI

doi:10.1016/j.jbc.2025.108266

Link

https://www.jbc.org/article/S0021-9258(25)00113-9/fulltext