Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells

The contribution of the B isoform of inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] 3-kinase (or ltpkb) and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P-4], its reaction product, to B cell function and development remains unknown. Here, we show that mice deficient in Itpkb have defects in B cell survival leading to specific and intrinsic developmental alterations in the B cell lineage and antigen unresponsiveness in vivo. The decreased B cell survival is associated with a decreased phosphorylation of Erk1/2 and increased Bim gene expression. B cell survival, development, and antigen responsiveness are normalized in parallel to reduced expression of Bim in ltpkb(-/-) Bim(+/-) mice. Analysis of the signaling pathway downstream of ltpkb revealed that Ins(1,3,4,5)P4 regulates subcellular distribution of Rasa3, a Ras GTPase-activating protein acting as an Ins(1,3,4,5)P-4 receptor. Together, our results indicate that Itpkb and Ins(1,3,4,5)P-4 mediate a survival signal in B cells via a Rasa3-Erk signaling pathway controlling proapoptotic Bim gene expression.