<italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers 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, includi...

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Autores principales:	Kyle Jarrod McLean, Marcelo Jacobs-Lorena
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Plasmodium TOR pathway malaria Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ba501a1bf5864ff1ab2fbcbd70fc8e2f
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spelling	oai:doaj.org-article:ba501a1bf5864ff1ab2fbcbd70fc8e2f2021-11-15T15:50:59Z<italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers Survival upon Amino Acid Starvation10.1128/mBio.02317-162150-7511https://doaj.org/article/ba501a1bf5864ff1ab2fbcbd70fc8e2f2017-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02317-16https://doaj.org/toc/2150-7511ABSTRACT 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 (PfMaf1) 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-tRNA synthesis under nutrient-limiting conditions, indicating that the function of Maf1 as a stress-responsive 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 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. 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 PfMaf1 is a component of a yet-to-be-described nutrient and stress response pathway.Kyle Jarrod McLeanMarcelo Jacobs-LorenaAmerican Society for MicrobiologyarticlePlasmodiumTOR pathwaymalariaMicrobiologyQR1-502ENmBio, Vol 8, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Plasmodium TOR pathway malaria Microbiology QR1-502
spellingShingle	Plasmodium TOR pathway malaria Microbiology QR1-502 Kyle Jarrod McLean Marcelo Jacobs-Lorena <italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers Survival upon Amino Acid Starvation
description	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 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 (PfMaf1) 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-tRNA synthesis under nutrient-limiting conditions, indicating that the function of Maf1 as a stress-responsive 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 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. 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 PfMaf1 is a component of a yet-to-be-described nutrient and stress response pathway.
format	article
author	Kyle Jarrod McLean Marcelo Jacobs-Lorena
author_facet	Kyle Jarrod McLean Marcelo Jacobs-Lorena
author_sort	Kyle Jarrod McLean
title	<italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers Survival upon Amino Acid Starvation
title_short	<italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers Survival upon Amino Acid Starvation
title_full	<italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers Survival upon Amino Acid Starvation
title_fullStr	<italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers Survival upon Amino Acid Starvation
title_full_unstemmed	<italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers Survival upon Amino Acid Starvation
title_sort	<italic toggle="yes">plasmodium falciparum maf1</italic> confers survival upon amino acid starvation
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/ba501a1bf5864ff1ab2fbcbd70fc8e2f
work_keys_str_mv	AT kylejarrodmclean italictoggleyesplasmodiumfalciparummaf1italicconferssurvivaluponaminoacidstarvation AT marcelojacobslorena italictoggleyesplasmodiumfalciparummaf1italicconferssurvivaluponaminoacidstarvation
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<italic toggle="yes">Plasmodium falciparum Maf1</italic> Confers Survival upon Amino Acid Starvation

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