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

PLoS Pathogens

Michal Zeituni-Molad¹  Moshe Ephros¹  Peter J. Myler²  Dan Zilberstein³  Caitlin Balno⁴  Adele Goldman-Pinkovich⁴  Rona Strasser⁵  Armando Jardim⁵  Doris Rentsch⁶  Martin Wiese⁷  Keren Bendelak⁸ 

[1] Carmel Medical Center and Faculty of Medicine, Technion,—Israel institute of Technology, Haifa, Israel;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;Faculty of Biology, Technion—Israel Institute of Technology, Haifa, Haifa, Israel;Institute of Parasitology, McGill University, Ste Anne de Bellevue, Quebec, Canada;Institute of Plant Sciences, University of Bern, Bern, Switzerland;Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom;The Smoler Proteomic Center, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel

关键词: Arginine;    Promastigotes;    Amastigotes;    Macrophages;    Leishmania;    Leishmania donovani;    Parasitic diseases;    Protein kinases;   

DOI  :  10.1371/journal.ppat.1005494

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY