title: An Arginine Deprivation Response Pathway Is Induced in Leishmania during Macrophage Invasion.
abstract: 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 produce metabolites (NO and polyamines) that constitute part of the host defense response and its suppression, respectively. We found that parasites respond to this shortage of arginine by up-regulating expression and activity of the Leishmania arginine transporter (LdAAP3), as well as several other transporters. Our analysis indicates the parasite monitors arginine levels in the environment rather than the intracellular pools. Phosphoproteomics and genetic analysis indicates that the arginine-deprivation response is mediated through a mitogen-activated protein kinase-2-dependent signaling cascade.
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Haifa, Israel.
authors.forename: Adele
authors.initials: A
authors.lastname: Goldman-Pinkovich
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Haifa, Israel.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Balno
authors.affiliation: Institute of Parasitology, McGill University, Ste Anne de Bellevue, Quebec, Canada.
authors.forename: Rona
authors.initials: R
authors.lastname: Strasser
authors.affiliation: Carmel Medical Center and Faculty of Medicine, Technion,-Israel institute of Technology, Haifa, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Zeituni-Molad
authors.affiliation: The Smoler Proteomic Center, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Bendelak
authors.affiliation: Institute of Plant Sciences, University of Bern, Bern, Switzerland.
authors.forename: Doris
authors.initials: D
authors.lastname: Rentsch
authors.affiliation: Carmel Medical Center and Faculty of Medicine, Technion,-Israel institute of Technology, Haifa, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Ephros
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Institute of Parasitology, McGill University, Ste Anne de Bellevue, Quebec, Canada.
authors.forename: Armando
authors.initials: A
authors.lastname: Jardim
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, Seattle, Washington, United States of America.|Departments of Global Health and Biomedical Informatics & Medical Education, University of Washington, Seattle, Washington, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Myler
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Haifa, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Zilberstein
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007893:Leishmania donovani / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D011073:Polyamines; D001120:Arginine; D020928:Mitogen-Activated Protein Kinases