A translational rheostat for RFLAT-1 regulates RANTES expression in T lymphocytes.
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.
Nikolcheva
Tania
T
Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, CCSR 2105, Stanford, CA 94305-5164, USA.
Pyronnet
Stephane
S
Chou
Szu-yi
SY
Sonenberg
Nahum
N
Song
An
A
Clayberger
Carol
C
Krensky
Alan M
AM
D016475:3T3 Cells; D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D039561:Eukaryotic Initiation Factor-4E; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D051741:Kruppel-Like Transcription Factors; D008213:Lymphocyte Activation; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D010448:Peptide Initiation Factors / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*
D020121:5' Untranslated Regions; D018797:Cell Cycle Proteins; D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; C486423:KLF13 protein, human; C486422:Klf13 protein, mouse; D051741:Kruppel-Like Transcription Factors; D010448:Peptide Initiation Factors; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA; C491395:MKNK1 protein, human; C106281:Mknk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases