Targeted extracellular signal-regulated kinase activation mediated by Leishmania amazonensis requires MP1 scaffold.
Leishmania amazonensis infection promotes alteration of host cellular signaling and intracellular parasite survival, but specific mechanisms are poorly understood. We previously demonstrated that L. amazonensis infection of dendritic cells (DC) activated extracellular signal-regulated kinase (ERK), an MAP-kinase kinase kinase, leading to altered DC maturation and non-healing cutaneous leishmaniasis. Studies using growth factors and cell lines have shown that targeted, robust, intracellular phosphorylation of ERK1/2 from phagolysosomes required recruitment and association with scaffolding proteins, including p14/MP1 and MORG1, on the surface of late endosomes. Based on the intracellular localization of L. amazonensis within a parasitophorous vacuole with late endosome characteristics, we speculated that scaffolding proteins would be important for intracellular parasite-mediated ERK signaling. Our findings demonstrate that MP1, MORG1, and ERK all co-localized on the surface of parasite-containing LAMP2-positive phagolysosomes. Infection of MEK1 mutant fibroblasts unable to bind MP1 demonstrated dramatically reduced ERK1/2 phosphorylation following L. amazonensis infection but not following positive control EGF treatment. This novel mechanism for localization of intracellular L. amazonensis-mediated ERK1/2 phosphorylation required the endosomal scaffold protein MP1 and localized to L. amazonensis parasitophorous vacuoles. Understanding how L. amazonensis parasites hijack host cell scaffold proteins to modulate signaling cascades provides targets for antiprotozoal drug development.
Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50010, USA.
Paola M
PM
Boggiatto
Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50010, USA.
Pedro A
PA
Martinez
Department of Pharmacology, LSU Health Sciences Center, New Orleans, LA 70112, USA.
Ashok
A
Pullikuth
Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50010, USA.
Douglas E
DE
Jones
Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA 50010, USA.
Bryan
B
Bellaire
Department of Pharmacology, LSU Health Sciences Center, New Orleans, LA 70112, USA; Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA 70112, USA.
Andrew
A
Catling
Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA 50010, USA; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA. Electronic address: tinyfeet15@yahoo.com.
Christine
C
Petersen
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000276:immunology / Q000469:parasitology; D054884:Host-Pathogen Interactions; D007894:Leishmania mexicana / Q000276:immunology*; D008247:Lysosomes / Q000737:chemistry / Q000469:parasitology; D008809:Mice, Inbred C3H; D010588:Phagosomes / Q000737:chemistry / Q000469:parasitology; D011506:Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C426009:LAMTOR2 protein, mouse; C487128:MORG1 protein, mouse; D011506:Proteins; D048049:Extracellular Signal-Regulated MAP Kinases
Dendritic cell; Leishmania; MAPK; MP1; Phagosome