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

J Clin Invest. 2002 Jul;110(1):119-26. doi: 10.1172/JCI15336.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • 5' Untranslated Regions
  • Animals
  • Base Sequence
  • Cell Cycle Proteins*
  • Cell Line
  • Chemokine CCL5 / metabolism*
  • DNA / genetics
  • DNA-Binding Proteins / genetics*
  • Eukaryotic Initiation Factor-4E
  • Humans
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Kruppel-Like Transcription Factors
  • Lymphocyte Activation
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • Peptide Initiation Factors / metabolism
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins*
  • Sequence Homology, Nucleic Acid
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Transcription Factors / genetics*

Substances

  • 5' Untranslated Regions
  • Cell Cycle Proteins
  • Chemokine CCL5
  • DNA-Binding Proteins
  • Eukaryotic Initiation Factor-4E
  • Intracellular Signaling Peptides and Proteins
  • KLF13 protein, human
  • Klf13 protein, mouse
  • Kruppel-Like Transcription Factors
  • Peptide Initiation Factors
  • RNA, Messenger
  • Repressor Proteins
  • Transcription Factors
  • DNA
  • MKNK1 protein, human
  • Mknk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases