title: CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR/4E-BP1.
abstract: The multistep, coordinated process of T-cell chemotaxis requires chemokines, and their chemokine receptors, to invoke signaling events to direct cell migration. Here, we examined the role for CCL5-mediated initiation of mRNA translation in CD4(+) T-cell chemotaxis. Using rapamycin, an inhibitor of mTOR, our data show the importance of mTOR in CCL5-mediated T-cell migration. Cycloheximide, but not actinomycin D, significantly reduced chemotaxis, suggesting a possible role for mRNA translation in T-cell migration. CCL5 induced phosphorylation/activation of mTOR, p70 S6K1, and ribosomal protein S6. In addition, CCL5 induced PI-3'K-, phospholipase D (PLD)-, and mTOR-dependent phosphorylation and deactivation of the transcriptional repressor 4E-BP1, which resulted in its dissociation from the eukaryotic initiation factor-4E (eIF4E). Subsequently, eIF4E associated with scaffold protein eIF4G, forming the eIF4F translation initiation complex. Indeed, CCL5 initiated active translation of mRNA, shown by the increased presence of high-molecular-weight polysomes that were significantly reduced by rapamycin treatment. Notably, CCL5 induced protein translation of cyclin D1 and MMP-9, known mediators of migration. Taken together, we describe a novel mechanism by which CCL5 influences translation of rapamycin-sensitive mRNAs and "primes" CD4(+) T cells for efficient chemotaxis.
authors.affiliation: Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON, Canada.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Murooka
authors.forename: Ramtin
authors.initials: R
authors.lastname: Rahbar
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Eleanor N
authors.initials: EN
authors.lastname: Fish
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D019938:Cyclin D1 / Q000096:biosynthesis; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010750:Phosphoproteins / Q000378:metabolism*; D014176:Protein Biosynthesis; D011506:Proteins; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D018946:Chemokine CCL5; C087000:EIF4EBP1 protein, human; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; D014157:Transcription Factors; D019938:Cyclin D1; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020780:Matrix Metalloproteinase 9