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A Polypyrimidine Tract-Binding Protein-Dependent Pathway of mRNA Stability Initiates with CpG Activation of Primary B Cells¹

Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854

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 D₂, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant PO1 AI-57596 from the National Institutes of Health and by The American Heart Association (to L.R.C.) and by a Postdoctoral Fellowship from the New Jersey Commission on Cancer Research (to J.F.P.).

² J.F.P. and S.V. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Lori R. Covey, Department of Cell Biology and Neuroscience, B314 Nelson Hall, Rutgers University, 604 Allison Road, Piscataway, NJ 08854. E-mail address: covey{at}biology.rutgers.edu

⁴ Abbreviations used in this paper: ARE, AU-rich element; PTB, polypyrimidine tract-binding; UTR, untranslated region; ODN, oligodeoxynucleotide; shRNA, short hairpin RNA.