Dataset Information

Arginine sensing in Leishmania

ABSTRACT: Abstract Protozoa of the genus Leishmania are the causative agents of leishmaniasis in humans. These parasites cycle between promastigotes in the sand fly mid-gut and amastigotes in phagolysosome of mammalian macrophages. During infection, they up-regulate host nitric oxide synthase and arginase expression, both of which use arginine as a substrate. These elevated activities deplete macrophage arginine pools, a situation that invading Leishmania must overcome since it is an essential amino acid. Leishmania donovani imports exogenous arginine via a mono-specific amino acid transporter (AAP3) and utilizes it primarily through the polyamine pathway to provide precursors for trypanothione biosynthesis. Here we report the discovery of a pathway whereby promastigote and amastigote forms of the Leishmania sense the lack of environmental arginine and respond with rapid up-regulation in AAP3 expression and activity, as well as several other transporters. Significantly, this arginine deprivation response is also activated in parasites during macrophage infection. Phosphoproteomic analyses of L. donovani promastigotes have implicated a mitogen activated protein kinase 2 (MPK2)-mediated signaling cascade in this response and L. mexicana mutants lacking MPK2 are unable to respond to arginine deprivation. In addition, these mutants cannot differentiate into amastigotes in axenic culture or in peritoneal macrophages, and fail to establish an infection in mice. We propose that sensing arginine levels plays a critical role in Leishmania virulence by activating a rapid metabolic reaction for salvaging this amino acid in response to the lower arginine concentration in the macrophage phagolysosome.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Leishmania Donovani

SUBMITTER: Keren Bendalak

LAB HEAD: Dan Zilberstein

PROVIDER: PXD002830 | Pride | 2016-04-11

REPOSITORIES: Pride

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An Arginine Deprivation Response Pathway Is Induced in Leishmania during Macrophage Invasion.

Goldman-Pinkovich Adele A Balno Caitlin C Strasser Rona R Zeituni-Molad Michal M Bendelak Keren K Rentsch Doris D Ephros Moshe M Wiese Martin M Jardim Armando A Myler Peter J PJ Zilberstein Dan D

PLoS pathogens 20160404 4

Amino acid sensing is an intracellular function that supports nutrient homeostasis, largely through controlled release of amino acids from lysosomal pools. The intracellular pathogen Leishmania resides and proliferates within human macrophage phagolysosomes. Here we describe a new pathway in Leishmania that specifically senses the extracellular levels of arginine, an amino acid that is essential for the parasite. During infection, the macrophage arginine pool is depleted due to its use to produc ...[more]

PMID: 27043018

Similar Datasets

Project description:Protozoa of the genus Leishmania are the causative agents of leishmaniasis in humans. These parasites cycle between promastigotes in the sand fly mid-gut and amastigotes in phagolysosome of mammalian macrophages. During infection, host up-regulate nitric oxide synthase and parasite induce host arginase expression, both of which use arginine as a substrate. These elevated activities deplete macrophage arginine pools, a situation that invading Leishmania must overcome since it is an essential amino acid. Leishmania donovani imports exogenous arginine via a mono-specific amino acid transporter (AAP3) and utilizes it primarily through the polyamine pathway to provide precursors for trypanothione biosynthesis. Here we report the discovery of a pathway whereby promastigote and amastigote forms of the Leishmania sense the lack of environmental arginine and respond with rapid up-regulation in AAP3 expression and activity, as well as several other transporters. Significantly, this arginine deprivation response is also activated in parasites during macrophage infection. Phosphoproteomic analyses of L. donovani promastigotes have implicated a Mitogen-Activated Protein Kinase 2 (MPK2)-mediated signaling cascade in this response and L. mexicana mutants lacking MPK2 are unable to respond to arginine deprivation. In this study, we established that Leishmania cells sense the absence of arginine in their environment; both in culture (axenic promastigotes and amastigotes) and in macrophages during infection (amastigotes). This study describes the first amino acid deprivation sensing mechanism and the pathway that transduce this response, and reveals a novel host-pathogen metabolic interplay. Total RNA from Ten Leishmania donovani samples were analyzed using RNA-Seq. Cells from two life stages (promastigotes and amastigotes) were grown in axenic culture in the presence and absense of arginine. For each condition two biological replicates were grown and analyzed. In addition two macrophage grown amastigotes were analyzed.

			Action	DRS
	33556-33574.msf	Msf
	33575-33578.msf	Msf
	33579-33583.msf	Msf
	33584-33588.msf	Msf
	33589-33607.msf	Msf