Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisinin
IntroductionMalaria parasites increasingly develop resistance to all drugs available in the market, hampering the goal of reducing malaria burden.MethodsHerein, we evaluated the impact of a single-nucleotide variant, E738K, present in the 26S proteasome regulatory subunit rpn2 gene, identified in Pl...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2024.1342856/full |
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| author | Adriana F. Gonçalves Adriana F. Gonçalves Ana Lima-Pinheiro Ana Lima-Pinheiro Miguel Teixeira Miguel Teixeira Miguel Teixeira Gustavo Capatti Cassiano Pedro Cravo Pedro E. Ferreira Pedro E. Ferreira |
| author_facet | Adriana F. Gonçalves Adriana F. Gonçalves Ana Lima-Pinheiro Ana Lima-Pinheiro Miguel Teixeira Miguel Teixeira Miguel Teixeira Gustavo Capatti Cassiano Pedro Cravo Pedro E. Ferreira Pedro E. Ferreira |
| author_sort | Adriana F. Gonçalves |
| collection | DOAJ |
| description | IntroductionMalaria parasites increasingly develop resistance to all drugs available in the market, hampering the goal of reducing malaria burden.MethodsHerein, 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 discussionThe 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. |
| first_indexed | 2024-03-08T04:06:35Z |
| format | Article |
| id | doaj.art-660c206067114734948c3e132a0d0834 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-03-08T04:06:35Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-660c206067114734948c3e132a0d08342024-02-09T05:00:05ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882024-02-011410.3389/fcimb.2024.13428561342856Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisininAdriana F. Gonçalves0Adriana F. Gonçalves1Ana Lima-Pinheiro2Ana Lima-Pinheiro3Miguel Teixeira4Miguel Teixeira5Miguel Teixeira6Gustavo Capatti Cassiano7Pedro Cravo8Pedro E. Ferreira9Pedro E. Ferreira10Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, PortugalLife and Health Sciences Research Institute (ICVS)/ Biomaterials, Biodegradables and Biomimetics Research Group (3B's)-PT Government Associate Laboratory, Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, PortugalLife and Health Sciences Research Institute (ICVS)/ Biomaterials, Biodegradables and Biomimetics Research Group (3B's)-PT Government Associate Laboratory, Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, PortugalLife and Health Sciences Research Institute (ICVS)/ Biomaterials, Biodegradables and Biomimetics Research Group (3B's)-PT Government Associate Laboratory, Braga, PortugalDepartment of Protection of Specific Crops, InnovPlantProtect Collaborative Laboratory, Elvas, PortugalGlobal Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health (LA-REAL), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Lisbon, PortugalGlobal Health and Tropical Medicine (GHTM), Associate Laboratory in Translation and Innovation Towards Global Health (LA-REAL), Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Lisbon, PortugalLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, PortugalLife and Health Sciences Research Institute (ICVS)/ Biomaterials, Biodegradables and Biomimetics Research Group (3B's)-PT Government Associate Laboratory, Braga, PortugalIntroductionMalaria parasites increasingly develop resistance to all drugs available in the market, hampering the goal of reducing malaria burden.MethodsHerein, 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 discussionThe 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.https://www.frontiersin.org/articles/10.3389/fcimb.2024.1342856/fullmalariaPlasmodium falciparumdrug resistanceproteasomegenetic engineeringartemisinin |
| spellingShingle | Adriana F. Gonçalves Adriana F. Gonçalves Ana Lima-Pinheiro Ana Lima-Pinheiro Miguel Teixeira Miguel Teixeira Miguel Teixeira Gustavo Capatti Cassiano Pedro Cravo Pedro E. Ferreira Pedro E. Ferreira Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisinin Frontiers in Cellular and Infection Microbiology malaria Plasmodium falciparum drug resistance proteasome genetic engineering artemisinin |
| title | Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisinin |
| title_full | Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisinin |
| title_fullStr | Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisinin |
| title_full_unstemmed | Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisinin |
| title_short | Mutation in the 26S proteasome regulatory subunit rpn2 gene in Plasmodium falciparum confers resistance to artemisinin |
| title_sort | mutation in the 26s proteasome regulatory subunit rpn2 gene in plasmodium falciparum confers resistance to artemisinin |
| topic | malaria Plasmodium falciparum drug resistance proteasome genetic engineering artemisinin |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2024.1342856/full |
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