Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance

Ruixue Xu, Lirong Lin, Zhiwei Jiao, Rui Liang, Yazhen Guo, Yixin Zhang, Xiaoxu Shang, Yuezhou Wang, Xu Wang, Luming Yao, Shengfa Liu, Xianming Deng, Jing Yuan (), Xin-zhuan Su () and Jian Li ()
Additional contact information
Ruixue Xu: Xiamen University
Lirong Lin: Xiamen University
Zhiwei Jiao: Xiamen University
Rui Liang: Xiamen University
Yazhen Guo: Xiamen University
Yixin Zhang: Xiamen University
Xiaoxu Shang: Xiamen University
Yuezhou Wang: Xiamen University
Xu Wang: Xiamen University
Luming Yao: Xiamen University
Shengfa Liu: Xiamen University
Xianming Deng: Xiamen University
Jing Yuan: Xiamen University
Xin-zhuan Su: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jian Li: Xiamen University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.

Date: 2024
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DOI: 10.1038/s41467-024-46006-3

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