title: Leishmania repression of host translation through mTOR cleavage is required for parasite survival and infection.
abstract: The protozoan parasite Leishmania alters the activity of its host cell, the macrophage. However, little is known about the effect of Leishmania infection on host protein synthesis. Here, we show that the Leishmania protease GP63 cleaves the mammalian/mechanistic target of rapamycin (mTOR), a serine/threonine kinase that regulates the translational repressor 4E-BP1. mTOR cleavage results in the inhibition of mTOR complex 1 (mTORC1) and concomitant activation of 4E-BP1 to promote Leishmania proliferation. Consistent with these results, pharmacological activation of 4E-BPs with rapamycin, results in a dramatic increase in parasite replication. In contrast, genetic deletion of 4E-BP1/2 reduces parasite load in macrophages ex vivo and decreases susceptibility to cutaneous leishmaniasis in vivo. The parasite resistant phenotype of 4E-BP1/2 double-knockout mice involves an enhanced type I IFN response. This study demonstrates that Leishmania evolved a survival mechanism by activating 4E-BPs, which serve as major targets for host translational control.
authors.affiliation: Department of Biochemistry and Goodman Cancer Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Maritza
authors.initials: M
authors.lastname: Jaramillo
authors.forename: Maria Adelaida
authors.initials: MA
authors.lastname: Gomez
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Marina Tiemi
authors.initials: MT
authors.lastname: Shio
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.forename: Irazú
authors.initials: I
authors.lastname: Contreras
authors.forename: Randi
authors.initials: R
authors.lastname: Luxenburg
authors.forename: Amy
authors.initials: A
authors.lastname: Rosenfeld
authors.forename: Rodney
authors.initials: R
authors.lastname: Colina
authors.forename: Robert W
authors.initials: RW
authors.lastname: McMaster
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D039642:Eukaryotic Initiation Factors; D006790:Host-Parasite Interactions; D018320:Leishmania major / Q000502:physiology*; D016773:Leishmaniasis, Cutaneous / Q000378:metabolism* / Q000469:parasitology; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania; D020123:Sirolimus