Involvement of Bik, a proapoptotic member of the Bcl-2 family, in surface IgM-mediated B cell apoptosis

Apoptosis plays a central role in shaping the repertoire of circulating mat ure B lymphocytes, but the underlying molecular mechanisms regulating B cel l fate are not well understood. Human B104 B lymphoma cells undergo apoptos is after surface Ig (sig)M, but not sIgD, ligation; sIgM-mediated apoptosis of B104 cells apparently requires new gene transcription because actinomyc in D can inhibit the apoptotic response. Here we report that expression of Bik, a proapoptotic member of the Bcl-2 family, is greatly increased after sIgM ligation. Bik expression was tightly controlled at both transcriptiona l and post-transcriptional levels. Whereas a calcineurin-dependent pathway was essential for Bik mRNA induction, both the phosphatidylinositol 3-kinas e (P13K)- and the calcineurin-dependent pathways were required for the sust ained production of Bik protein. Consistent with these findings, sIgD ligat ion, which leads to the similar calcium mobilization and increases in Bik m RNA, induced only a transient activation of PI3K and did not lead to sustai ned Bik protein expression. Furthermore, sustained Bik protein expression c orrelated with B cell apoptosis, as treatment with either a calcineurin inh ibitor or P13K inhibitors blocked both sIgM-mediated sustained Bik protein induction and apoptosis. In addition, sIgM ligation strongly increased the amount of Bik associated with endogenous Bcl-x, but sIgD ligation did not. Studies with caspase inhibitors also revealed that Bik and Bcl-x interacted upstream of caspases in the B cell apoptosis cascade. Thus, Bik protein in duction and, subsequently, sequestering of antiapoptotic Bcl-x by Bik may p lay an important role in regulating B cell apoptosis.