A translational rheostat for RFLAT-1 regulates RANTES expression in T lymphocytes

Tania Nikolcheva, Stephane Pyronnet, Szu Yi Chou, Nahum Sonenberg, An Song, Carol Clayberger, Alan M. Krensky*

*Corresponding author for this work

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Activation of T lymphocytes by specific antigen triggers a 3- to 7-day maturation process. Terminal differentiation begins late after T cell activation and involves expression of effector genes, including the chemokine RANTES and its major transcriptional regulator, RANTES factor of late-activated T lymphocytes-1 (RFLAT-1). In this article we demonstrate that RFLAT-1 expression is translationally regulated through its 5′-UTR and in a cell type-specific manner. Overexpression of the translation initiation factor eIF4E increases RFLAT-1 protein, while inhibition of Mnk1, which phosphorylates eIF4E, reduces RFLAT-1 production, indicating cap-dependent translational regulation. These events are regulated by ERK-1/2 and p38 MAP kinases and allow T cells to rapidly adjust RANTES expression in response to changes in the cellular environment, such as stress and/or growth factors. These findings provide a molecular mechanism for a rheostat effect of increasing or decreasing RANTES expression at sites of inflammation. Memory T cells, already poised to make RANTES, are finely regulated by translational control of the major transcription factor regulating RANTES expression. This is the first example of such a mechanism regulating a chemokine, but it seems likely that this will prove to be a general way for cells to rapidly respond to stress, cytokines, and other proinflammatory factors in their local environment.

Original languageEnglish (US)
Pages (from-to)119-126
Number of pages8
JournalJournal of Clinical Investigation
Volume110
Issue number1
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Medicine(all)

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    Nikolcheva, T., Pyronnet, S., Chou, S. Y., Sonenberg, N., Song, A., Clayberger, C., & Krensky, A. M. (2002). A translational rheostat for RFLAT-1 regulates RANTES expression in T lymphocytes. Journal of Clinical Investigation, 110(1), 119-126. https://doi.org/10.1172/JCI0215336