A Plasmodium falciparum RING Finger E3 Ubiquitin Ligase Modifies the Roles of PfMDR1 and PfCRT in Parasite Drug Responses.
Antimicrob Agents Chemother
; 67(2): e0082122, 2023 02 16.
Article
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| MEDLINE
| ID: mdl-36625569
ABSTRACT
Protein ubiquitination is an important posttranslational regulation mechanism that mediates Plasmodium development and modifies parasite responses to antimalarial drugs. Although mutations in several parasite ubiquitination enzymes have been linked to increased drug tolerance, the molecular mechanisms by which ubiquitination pathways mediate these parasite responses remain largely unknown. Here, we investigate the roles of a Plasmodium falciparum ring finger ubiquitin ligase (PfRFUL) in parasite development and in responses to antimalarial drugs. We engineered a transgenic parasite having the Pfrful gene tagged with an HA-2A-NeoR-glmS sequence to knockdown (KD) Pfrful expression using glucosamine (GlcN). A Western blot analysis of the proteins from GlcN-treated pSLI-HA-NeoR-glmS-tagged (PfRFULg) parasites, relative to their wild-type (Dd2) controls, showed changes in the ubiquitination of numerous proteins. PfRFUL KD rendered the parasites more sensitive to multiple antimalarial drugs, including mefloquine, piperaquine, amodiaquine, and dihydroartemisinin. PfRFUL KD also decreased the protein level of the P. falciparum multiple drug resistance 1 protein (PfMDR1) and altered the ratio of two bands of the P. falciparum chloroquine resistance transporter (PfCRT), suggesting contributions to the changed drug responses by the altered ubiquitination of these two molecules. The inhibition of proteasomal protein degradation by epoxomicin increased the PfRFUL level, suggesting the degradation of PfRFUL by the proteasome pathways, whereas the inhibition of E3 ubiquitin ligase activities by JNJ26854165 reduced the PfRFUL level. This study reveals the potential mechanisms of PfRFUL in modifying the expression of drug transporters and their roles in parasite drug responses. PfRFUL could be a potential target for antimalarial drug development.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
2_ODS3
/
3_ND
Problema de salud:
2_enfermedades_transmissibles
/
3_malaria
/
3_neglected_diseases
Asunto principal:
Plasmodium falciparum
/
Proteínas Protozoarias
/
Ubiquitina-Proteína Ligasas
/
Antimaláricos
Límite:
Humans
Idioma:
En
Revista:
Antimicrob Agents Chemother
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos