A Polypyrimidine Tract-Binding Protein-Dependent Pathway of mRNA Stability Initiates with CpG Activation of Primary B Cells

The mRNA encoding CD154, a critical protein involved in both humoral and cell-mediated immune responses, is regulated at the posttranscriptional level by the binding of complex I, a polypyrimidine tract-binding (PTB) protein-containing complex, which acts to increase message stability at late times...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2008-09, Vol.181 (5), p.3336-3345
Main Authors: Porter, Joseph F, Vavassori, Stefano, Covey, Lori R
Format: Article
Language:English
Subjects:
B-Lymphocytes - immunology
Binding Sites
Cells, Cultured
Cyclin D2
Cyclins - genetics
Cyclins - metabolism
Dinucleoside Phosphates - physiology
Gene Expression Profiling
Humans
Lymphocyte Activation
Polypyrimidine Tract-Binding Protein - metabolism
Protein Binding
rab GTP-Binding Proteins - genetics
rab GTP-Binding Proteins - metabolism
RNA Stability
RNA, Messenger - analysis
RNA, Messenger - metabolism
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Summary:The mRNA encoding CD154, a critical protein involved in both humoral and cell-mediated immune responses, is regulated at the posttranscriptional level by the binding of complex I, a polypyrimidine tract-binding (PTB) protein-containing complex, which acts to increase message stability at late times of activation. Our current work focuses on analyzing a similar complex in B cells, designated B-cpx I, which is increased in B cells activated by CpG engagement of the TLR9 receptor but not by activation through CD40. Expression profiling of transcripts from primary B cells identified 31 mRNA transcripts with elevated PTB binding upon activation. Two of these transcripts, Rab8A and cyclin D(2), contained binding sites for B-cpx I in their 3' untranslated regions (UTRs). Analysis of turnover of endogenous Rab8A transcript in B cells revealed that like CD154, the mRNA half-life increased following activation and insertion of the Rab8A B-cpx I binding site into a heterologous transcript led to a 3-fold increase in stability. Also, short hairpin RNA down-regulation of PTB resulted in a corresponding decrease in Rab8A mRNA half-life. Overall these data strongly support a novel pathway of mRNA turnover that is expressed both in T cells and B cells and depends on the formation of a PTB-containing stability complex in response to cellular activation.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.181.5.3336