Stim1 sets a threshold for activation of a pro-apoptotic Erk pathway in B cells (84.21)

Abstract

Abstract Developing B cells differ from mature B cells in signaling downstream of the B cell receptor (BCR), and these differences play a crucial role in repertoire selection. While BCR crosslinking in mature B cells leads to proliferation and activation, in immature B cells it triggers apoptosis. BCR-induced Ca2+ entry is higher and prolonged in immature B cells with respect to mature B cells. While it is known that differences in Ca2+ signals play a role in the differing BCR responses during B cell development, the exact signaling pathways involved in the apoptosis vs. proliferation decision remain elusive. Stim1 is a Ca2+ sensor that is required for gating of the CRAC channels, and its expression is transiently increased during B cell development. We demonstrate that increasing Stim1 expression is sufficient to augment the amplitude and duration of Ca2+ entry in B cells, and consequently sensitizes B cells to antigen-induced apoptosis. Increased intracellular Ca2+ activates a pro-apoptotic, Ca2+-dependent pathway to Erk, and the biochemical requirements for Ca2+-dependent Erk activation differ from those of diacyl glycerol (DAG)-mediated Erk activation. In immature B cells, increases in Ca2+ entry that outlast increases in DAG levels may lead to activation of pro-apoptotic, Ca2+-dependent ERK signals that override DAG-mediated proliferative signals, thereby triggering negative selection.