E3 ubiquitin ligase Fbw7 regulates B cell survival and T cell-independent responses

Abstract

Abstract B cells continuously populate peripheral organs to maintain a large number of diverse mature B cell clones. These cells have controlled temporal boundaries and await their potential activation in a naïve resting state. Newly emerging B cells are maintained by survival signals while previous B cell generations die through apoptosis. During activation, B cells alter their metabolic machinery to enable categorical fate decisions. The E3 ubiquitin ligase, Fbw7, mandates proteasomal degradation of several oncogenes involved in cellular proliferation, growth, and survival. To elucidate the role of Fbw7 in B cells, we studied the function of Fbw7 in a conditional knockout mouse model. Ablation of Fbw7 during early B cell development diminished the mature recirculating B cell pool in the bone marrow and decreased the B cell population in the spleen. Further, we found a drastic reduction of the B1 cells in the peritoneal cavity. These unexpected results prompted us to generate a novel acute deletion model for Fbw7 to study mature B1 and B2 cells. Acute deletion of Fbw7 confirmed reduction of B cell population within a few weeks. When challenged with T cell-independent antigens the overall antibody responses were reduced. BCR-stimulation of B cells ex vivo showed reduced calcium signaling, poor proliferation potential and upregulation of apoptosis in knockout cells. Ectopic expression of BCL2 in B cells, partially rescued the apoptotic fate of these cells. Our results indicate for the first time that Fbw7 is a critical regulator in B cells, contributing to survival signaling and modulating B cell responses.