TY - JOUR
T1 - Plasmodium falciparum Maf1 confers survival upon amino acid starvation
AU - McLean, Kyle Jarrod
AU - Jacobs-Lorena, Marcelo
N1 - Funding Information:
We thank John Adams, David Fidock, Didier Ménard, and the BEI Resources for sharing parasite lines. We also thank the laboratories of David Fidock and Manoj Duraisingh for transfection assistance. We thank Abhai Tripathi and the Johns Hopkins Malaria Research Institute for supplying human blood for parasite culture. K.J.M. was supported by a Johns Hopkins Malaria Research Institute (JHMRI) predoctoral fellowship. This research was supported by NIH grant R21-AI67640 and by a JHMRI pilot grant. Additional support was provided by the Johns Hopkins Malaria Research Institute and the Bloomberg Family Foundation. Supply of human blood was supported by NIH grant RR00052. The funders had no part in the design of experiments, the collection of data, or the decision to submit the manuscript for publication.
Publisher Copyright:
© 2017 McLean and Jacobs-Lorena.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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 central TOR kinase, have been lost in the apicomplexan lineage, and it is unknown how these organisms detect and respond to nutrient starvation in its absence. Plasmodium falciparum encodes a putative ortholog of the RNA polymerase (Pol) III repressor Maf1, 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 P. falciparum Maf1 (Pf Maf1) in regulating RNA Pol III expression under conditions of nutrient starvation and other stresses. Using a transposon insertion mutant with an altered Maf1 expression profile, we demonstrated that proper Maf1 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 Maf1 mutant is defective in the downregulation of pre-t RNA synthesis under nutrient-limiting conditions, indicating that the function of Maf1 as a stressresponsive regulator of structural RNA transcription is conserved in P. falciparum. Recent work has demonstrated that parasites carrying artemisinin-resistant K13 alleles display an enhanced ability to recover from drug-induced growth retardation. We show that one such artemisinin-resistant line displays greater regulation of pret RNA expression and higher survival upon prolonged amino acid starvation, suggesting that overlapping, Pf Maf1-associated pathways may regulate growth recovery from both artemisinin treatment and amino acid starvation. IMPORTANCE Eukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. The TOR 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 Plasmodium falciparum appears to have lost the TOR 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 TOR 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 Pf Maf1 is a component of a yet-tobe-described nutrient and stress response pathway.
AB - 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 central TOR kinase, have been lost in the apicomplexan lineage, and it is unknown how these organisms detect and respond to nutrient starvation in its absence. Plasmodium falciparum encodes a putative ortholog of the RNA polymerase (Pol) III repressor Maf1, 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 P. falciparum Maf1 (Pf Maf1) in regulating RNA Pol III expression under conditions of nutrient starvation and other stresses. Using a transposon insertion mutant with an altered Maf1 expression profile, we demonstrated that proper Maf1 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 Maf1 mutant is defective in the downregulation of pre-t RNA synthesis under nutrient-limiting conditions, indicating that the function of Maf1 as a stressresponsive regulator of structural RNA transcription is conserved in P. falciparum. Recent work has demonstrated that parasites carrying artemisinin-resistant K13 alleles display an enhanced ability to recover from drug-induced growth retardation. We show that one such artemisinin-resistant line displays greater regulation of pret RNA expression and higher survival upon prolonged amino acid starvation, suggesting that overlapping, Pf Maf1-associated pathways may regulate growth recovery from both artemisinin treatment and amino acid starvation. IMPORTANCE Eukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. The TOR 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 Plasmodium falciparum appears to have lost the TOR 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 TOR 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 Pf Maf1 is a component of a yet-tobe-described nutrient and stress response pathway.
KW - Malaria
KW - Plasmodium
KW - TOR pathway
UR - http://www.scopus.com/inward/record.url?scp=85019093570&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019093570&partnerID=8YFLogxK
U2 - 10.1128/mBio.02317-16
DO - 10.1128/mBio.02317-16
M3 - Article
C2 - 28351924
AN - SCOPUS:85019093570
SN - 2161-2129
VL - 8
JO - mBio
JF - mBio
IS - 2
M1 - e02317-16
ER -