Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance
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..
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Nature Communications - 15(2024), 1, Seite 14 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ruixue Xu [VerfasserIn] |
|---|
| Links: |
doi.org [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1038/s41467-024-46006-3 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
DOAJ09117838X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | DOAJ09117838X | ||
| 003 | DE-627 | ||
| 005 | 20240414051557.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240412s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-024-46006-3 |2 doi | |
| 035 | |a (DE-627)DOAJ09117838X | ||
| 035 | |a (DE-599)DOAJ3b3cdffaf762482398a137bfe06c0188 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 0 | |a Ruixue Xu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a 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. | ||
| 653 | 0 | |a Science | |
| 653 | 0 | |a Q | |
| 700 | 0 | |a Lirong Lin |e verfasserin |4 aut | |
| 700 | 0 | |a Zhiwei Jiao |e verfasserin |4 aut | |
| 700 | 0 | |a Rui Liang |e verfasserin |4 aut | |
| 700 | 0 | |a Yazhen Guo |e verfasserin |4 aut | |
| 700 | 0 | |a Yixin Zhang |e verfasserin |4 aut | |
| 700 | 0 | |a Xiaoxu Shang |e verfasserin |4 aut | |
| 700 | 0 | |a Yuezhou Wang |e verfasserin |4 aut | |
| 700 | 0 | |a Xu Wang |e verfasserin |4 aut | |
| 700 | 0 | |a Luming Yao |e verfasserin |4 aut | |
| 700 | 0 | |a Shengfa Liu |e verfasserin |4 aut | |
| 700 | 0 | |a Xianming Deng |e verfasserin |4 aut | |
| 700 | 0 | |a Jing Yuan |e verfasserin |4 aut | |
| 700 | 0 | |a Xin-zhuan Su |e verfasserin |4 aut | |
| 700 | 0 | |a Jian Li |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i In |t Nature Communications |d Nature Portfolio, 2016 |g 15(2024), 1, Seite 14 |w (DE-627)DOAJ000041114 |x 20411723 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2024 |g number:1 |g pages:14 |
| 856 | 4 | 0 | |u https://doi.org/10.1038/s41467-024-46006-3 |z kostenfrei |
| 856 | 4 | 0 | |u https://doaj.org/article/3b3cdffaf762482398a137bfe06c0188 |z kostenfrei |
| 856 | 4 | 0 | |u https://doi.org/10.1038/s41467-024-46006-3 |z kostenfrei |
| 856 | 4 | 2 | |u https://doaj.org/toc/2041-1723 |y Journal toc |z kostenfrei |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_DOAJ | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2024 |e 1 |h 14 | ||