tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum.

Autor: Small-Saunders JL; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. jls2302@cumc.columbia.edu.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA. jls2302@cumc.columbia.edu., Sinha A; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.; Antimicrobial Resistance IRG, Singapore MIT Alliance for Research and Technology, Singapore, Singapore., Bloxham TS; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA., Hagenah LM; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA., Sun G; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Preiser PR; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.; Antimicrobial Resistance IRG, Singapore MIT Alliance for Research and Technology, Singapore, Singapore., Dedon PC; Antimicrobial Resistance IRG, Singapore MIT Alliance for Research and Technology, Singapore, Singapore.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Fidock DA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. df2260@cumc.columbia.edu.; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA. df2260@cumc.columbia.edu.; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA. df2260@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2024 Jun; Vol. 9 (6), pp. 1483-1498. Date of Electronic Publication: 2024 Apr 17.
DOI: 10.1038/s41564-024-01664-3
Abstrakt: Plasmodium falciparum artemisinin (ART) resistance is driven by mutations in kelch-like protein 13 (PfK13). Quiescence, a key aspect of resistance, may also be regulated by a yet unidentified epigenetic pathway. Transfer RNA modification reprogramming and codon bias translation is a conserved epitranscriptomic translational control mechanism that allows cells to rapidly respond to stress. We report a role for this mechanism in ART-resistant parasites by combining tRNA modification, proteomic and codon usage analyses in ring-stage ART-sensitive and ART-resistant parasites in response to drug. Post-drug, ART-resistant parasites differentially hypomodify mcm 5 s 2 U on tRNA and possess a subset of proteins, including PfK13, that are regulated by Lys codon-biased translation. Conditional knockdown of the terminal s 2 U thiouridylase, PfMnmA, in an ART-sensitive parasite background led to increased ART survival, suggesting that hypomodification can alter the parasite ART response. This study describes an epitranscriptomic pathway via tRNA s 2 U reprogramming that ART-resistant parasites may employ to survive ART-induced stress.
(© 2024. The Author(s).)
Databáze: MEDLINE
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