PMID- 21501832
OWN - NLM
STAT- MEDLINE
DCOM- 20111019
LR  - 20211203
IS  - 1934-6069 (Electronic)
IS  - 1931-3128 (Linking)
VI  - 9
IP  - 4
DP  - 2011 Apr 21
TI  - Leishmania repression of host translation through mTOR cleavage is required for 
      parasite survival and infection.
PG  - 331-41
LID - 10.1016/j.chom.2011.03.008 [doi]
AB  - 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.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Jaramillo, Maritza
AU  - Jaramillo M
AD  - Department of Biochemistry and Goodman Cancer Center, McGill University, 
      Montreal, Quebec, Canada.
FAU - Gomez, Maria Adelaida
AU  - Gomez MA
FAU - Larsson, Ola
AU  - Larsson O
FAU - Shio, Marina Tiemi
AU  - Shio MT
FAU - Topisirovic, Ivan
AU  - Topisirovic I
FAU - Contreras, Irazu
AU  - Contreras I
FAU - Luxenburg, Randi
AU  - Luxenburg R
FAU - Rosenfeld, Amy
AU  - Rosenfeld A
FAU - Colina, Rodney
AU  - Colina R
FAU - McMaster, Robert W
AU  - McMaster RW
FAU - Olivier, Martin
AU  - Olivier M
FAU - Costa-Mattioli, Mauro
AU  - Costa-Mattioli M
FAU - Sonenberg, Nahum
AU  - Sonenberg N
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Host Microbe
JT  - Cell host & microbe
JID - 101302316
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.- (glycoprotein gp63, Leishmania)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Cell Host Microbe. 2011 Apr 21;9(4):257-9. PMID: 21501824
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Carrier Proteins/genetics/metabolism
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Eukaryotic Initiation Factors
MH  - *Host-Parasite Interactions
MH  - Leishmania major/*physiology
MH  - Leishmaniasis, Cutaneous/*metabolism/parasitology
MH  - Macrophages/*metabolism/parasitology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Metalloendopeptidases/metabolism
MH  - Mice
MH  - Multiprotein Complexes
MH  - Phosphoproteins/genetics/metabolism
MH  - Polymerase Chain Reaction
MH  - Protein Biosynthesis
MH  - Proteins/metabolism
MH  - Sequence Deletion
MH  - Signal Transduction/genetics
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
EDAT- 2011/04/20 06:00
MHDA- 2011/10/20 06:00
CRDT- 2011/04/20 06:00
PHST- 2009/12/05 00:00 [received]
PHST- 2010/10/01 00:00 [revised]
PHST- 2011/03/04 00:00 [accepted]
PHST- 2011/04/20 06:00 [entrez]
PHST- 2011/04/20 06:00 [pubmed]
PHST- 2011/10/20 06:00 [medline]
AID - S1931-3128(11)00095-3 [pii]
AID - 10.1016/j.chom.2011.03.008 [doi]
PST - ppublish
SO  - Cell Host Microbe. 2011 Apr 21;9(4):331-41. doi: 10.1016/j.chom.2011.03.008.