<i>Plasmodium falciparum Maf1</i> Confers Survival upon Amino Acid Starvation

Abstract

The target of rapamycin complex 1 (<i>TORC1</i>) 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 central <i>TOR</i> kinase, have been lost in the apicomplexan lineage, and it is unknown how these organisms detect and respond to nutrient starvation in its absence. <i>Plasmodium falciparum</i> encodes a putative ortholog of the RNA polymerase (Pol) III repressor <i>Maf1</i>, which has been demonstrated to modulate Pol III transcription in a TOR-dependent manner in a number of organisms. Here, we investigate the role of <i>P. falciparum Maf1</i> (<i>PfMaf1</i>) in regulating RNA Pol III expression under conditions of nutrient starvation and other stresses. Using a transposon insertion mutant with an altered <i>Maf1</i> expression profile, we demonstrated that proper <i>Maf1</i> expression 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. This <i>Maf1</i> mutant is defective in the downregulation of pre-tRNA synthesis under nutrient-limiting conditions, indicating that the function of <i>Maf1</i> as a stress-responsive regulator of structural RNA transcription is conserved in <i>P. falciparum</i> Recent work has demonstrated that parasites carrying artemisinin-resistant <i>K13</i> alleles 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, <i>Pf</i>Maf1-associated pathways may regulate growth recovery from both artemisinin treatment and amino acid starvation.<b>IMPORTANCE</b> Eukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. The <i>TOR</i> pathway 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 parasite <i>Plasmodium falciparum</i> appears to have lost the <i>TOR</i> pathway 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 by <i>TOR</i> in other eukaryotes, plays an important role in maintaining the parasite's viability in the face of starvation and other forms of stress. This suggests that <i>PfMaf1</i> is a component of a yet-to-be-described nutrient and stress response pathway.