CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR/4E-BP1

TT Murooka, R Rahbar, LC Platanias… - Blood, The Journal of …, 2008 - ashpublications.org
TT Murooka, R Rahbar, LC Platanias, EN Fish
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
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 …
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.
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