title: Plasmodium falciparum Maf1Confers Survival upon Amino Acid Starvation.
abstract: The target of rapamycin complex 1 (TORC1) pathway is a highly conserved signaling pathway across eukaryotes that integrates nutrient and stress signals to regulate the cellular growth rate and the transition into and maintenance of dormancy. The majority of the pathway's components, including the centralTORkinase, have been lost in the apicomplexan lineage, and it is unknown how these organisms detect and respond to nutrient starvation in its absence.Plasmodium falciparumencodes a putative ortholog of the RNA polymerase (Pol) III repressorMaf1, which has been demonstrated to modulate Pol III transcription in a TOR-dependent manner in a number of organisms. Here, we investigate the role ofP. falciparum Maf1(PfMaf1) in regulating RNA Pol III expression under conditions of nutrient starvation and other stresses. Using a transposon insertion mutant with an alteredMaf1expression profile, we demonstrated that properMaf1expression is necessary for survival of the dormancy-like state induced by prolonged amino acid starvation and is needed for full recovery from other stresses that slow or stall the parasite cell cycle. ThisMaf1mutant is defective in the downregulation of pre-tRNA synthesis under nutrient-limiting conditions, indicating that the function ofMaf1as a stress-responsive regulator of structural RNA transcription is conserved inP. falciparumRecent work has demonstrated that parasites carrying artemisinin-resistantK13alleles display an enhanced ability to recover from drug-induced growth retardation. We show that one such artemisinin-resistant line displays greater regulation of pre-tRNA expression and higher survival upon prolonged amino acid starvation, suggesting that overlapping,PfMaf1-associated pathways may regulate growth recovery from both artemisinin treatment and amino acid starvation.IMPORTANCEEukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. TheTORpathway is a well-studied signaling pathway found throughout eukaryotes that is known to integrate a variety of signals to regulate organismal growth in response to starvation and other stresses. The human malaria parasitePlasmodium falciparumappears to have lost theTORpathway over the course of evolution, and it is unclear how the parasite modulates its growth in response to starvation and drug treatment. Here, we show that Maf1, a protein regulated byTORin other eukaryotes, plays an important role in maintaining the parasite's viability in the face of starvation and other forms of stress. This suggests thatPfMaf1is a component of a yet-to-be-described nutrient and stress response pathway.
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Malaria Research Institute, Baltimore, Maryland, USA.
authors.forename: Kyle Jarrod
authors.initials: KJ
authors.lastname: McLean
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Malaria Research Institute, Baltimore, Maryland, USA ljacob13@jhu.edu.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Jacobs-Lorena
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D002470:Cell Survival; D004251:DNA Transposable Elements; D005786:Gene Expression Regulation; D016254:Mutagenesis, Insertional; D009154:Mutation; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D012320:RNA Polymerase III / Q000096:biosynthesis*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D004251:DNA Transposable Elements; D015800:Protozoan Proteins; D012097:Repressor Proteins; D012320:RNA Polymerase III
keywords: Plasmodium; TOR pathway; malaria