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, Jian Li
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...
February 27, 2024: Nature Communications