Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisinin.

Adriana F Gonçalves, Ana Lima-Pinheiro, Miguel Teixeira, Gustavo Capatti Cassiano, Pedro Cravo, Pedro E Ferreira

Research output: Contribution to journalArticlepeer-review

Abstract

INTRODUCTION: Malaria parasites increasingly develop resistance to all drugs available in the market, hampering the goal of reducing malaria burden.

METHODS: Herein, we evaluated the impact of a single-nucleotide variant, E738K, present in the 26S proteasome regulatory subunit rpn2 gene, identified in Plasmodium chabaudi resistant parasites. Plasmids carrying a functional rpn2 interspecies chimeric gene with 5' recombination region from P. falciparum and 3' from P. chabaudi were constructed and transfected into Dd2 P. falciparum parasites.

RESULTS AND DISCUSSION: The 738K variant parasite line presented increased parasite survival when subjected to dihydroartemisinin (DHA), as well as increased chymotrypsin-like activity and decreased accumulation of polyubiquitinated proteins. We thus conclude that the ubiquitin-proteasome pathway, including the 738K variant, play an important role in parasite response to DHA, being the first report of a mutation in a potential DHA drug target enhancing parasite survival and contributing to a significant advance in the understanding the biology of artemisinin resistance.

Original languageEnglish
Article number1342856
Pages (from-to)1342856
JournalFrontiers in Cellular and Infection Microbiology
Volume14
DOIs
Publication statusPublished - 2024

Keywords

  • Humans
  • Plasmodium falciparum/genetics
  • Proteasome Endopeptidase Complex/genetics
  • Antimalarials/pharmacology
  • Artemisinins/pharmacology
  • Malaria, Falciparum/parasitology
  • Mutation
  • Protozoan Proteins/genetics

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