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Selection of the Alternative Exon 1 from the cd5 Gene Down-Regulates Membrane Level of the Protein in B Lymphocytes¹

Soizic Garaud^*, Christelle Le Dantec^*, Christian Berthou, Peter M. Lydyard, Pierre Youinou^2,* and Yves Renaudineau^*

^* Laboratory of Immunology and Department of Hematology, Brest University Medical School, Brest, France; and School of Biosciences, University of Westminster, London, United Kingdom

The human cd5 gene has two alternative exons 1: exon 1A (E1A) which encodes the full-length (FL) CD5 protein and exon 1B (E1B) which encodes a truncated (TR) isoform. The FL variant of CD5 protein is translocated to the plasma membrane, while its TR variant is retained in the cytoplasm. Because there is an inverse relationship between the levels of FL-CD5 and TR-CD5 in B cells, we have addressed the issue of how the selection of exon 1 is determined. In leukemic B cells, DNA methyltransferase (DNMT)1-induced methylation of E1B prevents its transcription. Furthermore, the level of mRNA for DNMT1 correlates inversely with that of mRNA for CD5-E1B. However, suppression of E1B transcription is incomplete, and some molecules of TR-CD5 continue to be synthesized. Bortezomid-induced inhibition of the proteasome establishes that these TR-CD5 molecules are cleared through the ubiquitin-proteasome pathway. Transfection of CD5 mutants into COS-1 cells locates the ubiquitin-binding site at the second destruction box of the extracellular region of CD5. Activation of the B cells by anti-IgM, Staphylococcus aureus Cowan I (SAC), or PMA up-regulates DNMT1, and thereby CD5-E1A mRNA at the expense of CD5-E1B mRNA. Aberrant synthesis of TR-CD5 is thus offset by balanced degradation of excessive protein. Dysregulation of these mechanisms reduces the expression level of membrane CD5, and thereby diminishes the threshold of the response by cells expressing CD5.

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¹ This work was supported by grants from the Conseil Régional de Bretagne, the Conseil Général du Finistère, and the French Ministry for Education and Research.

² Address correspondence and reprint requests to Prof. Pierre Youinou at Laboratory of Immunology, Brest University Medical School, BP824, F29609 Brest, France. E-mail address: Youinou{at}univ-brest.fr

³ Abbreviations used in this paper: HERV, human endogenous retrovirus; E1A, exon 1A; E1B, exon 1B; FL, full-length; TR, truncated; DNMT, DNA methyltransferase; CLL, chronic lymphocytic leukemia; UBS, ubiquitin-binding site; PcA, procainamide; aza, 5-azacytidine; BTZ, bortezomid; MFI, mean fluorescence intensity; RFP, red fluorescent protein; SAC, Staphylococcus aureus Cowan I.