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B Cell Receptor-Mediated Apoptosis of Human Lymphocytes Is Associated with a New Regulatory Pathway of Bim Isoform Expression¹

Shahul Mouhamad^*, Laurence Besnault^*, Marie Thérèse Auffredou^*, Corinne Leprince, Marie Françoise Bourgeade^*, Gérald Leca^*, and Aimé Vazquez^2,*

^* Institut National de la Santé et de la Recherche Médicale Unité 542, Villejuif, France; Association Claude Bernard, Hopital Paul Brousse, Villejuif, France; and Institut National de la Santé et de la Recherche Médicale Unité 248, Institut Curie, Paris, France

Studies in Bim-deficient mice have shown that the proapoptotic molecule Bim plays a key role in the control of B cell homeostasis and activation. However, the role of Bim in human B lymphocyte apoptosis is unknown. We show in this study that, depending on the degree of cross-linking, B cell receptors can mediate both Bim-dependent and apparent Bim-independent apoptotic pathways. Cross-linked anti-µ Ab-mediated activation induces an original pathway governing the expression of the various Bim isoforms. This new pathway involves the following three sequential steps: 1) extracellular signal-regulated kinase-dependent phosphorylation of the BimEL isoform, which is produced in large amounts in healthy B cells; 2) proteasome-mediated degradation of phosphorylated BimEL; and 3) increased expression of the shorter apoptotic isoforms BimL and BimS.

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