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

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1342856

DOI=10.3389/fcimb.2024.1342856

ISSN=2235-2988

ABSTRACT=<sec><title>Introduction</title><p>Malaria parasites increasingly develop resistance to all drugs available in the market, hampering the goal of reducing malaria burden.</p></sec><sec><title>Methods</title><p>Herein, we evaluated the impact of a single-nucleotide variant, E738K, present in the 26S proteasome regulatory subunit <italic>rpn2</italic> gene, identified in <italic>Plasmodium chabaudi</italic> resistant parasites. Plasmids carrying a functional <italic>rpn2</italic> interspecies chimeric gene with 5’ recombination region from <italic>P. falciparum</italic> and 3’ from <italic>P. chabaudi</italic> were constructed and transfected into Dd2 <italic>P. falciparum</italic> parasites.</p></sec><sec><title>Results and discussion</title><p>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.</p></sec>