Production of Ins(1,3,4,5)P4 mediated by the kinase Itpkb inhibits store-operated calcium channels and regulates B cell selection and activation

Abstract

Antigen receptor-mediated production of inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) in lymphocytes triggers the release of Ca2+ from intracellular stores; this release of Ca2+ results in the opening of store-operated Ca2+ channels in the plasma membrane. Here we report that mice lacking Ins(1,4,5)P3 3-kinase B (Itpkb), which converts Ins(1,4,5)P3 to inositol-1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), had impaired B lymphocyte development and defective immunoglobulin G3 antibody responses to a T lymphocyte-independent antigen. Itpkb-deficient B lymphocytes had the phenotypic and functional features of tolerant B lymphocytes and showed enhanced activity of store-operated Ca2+ channels after B lymphocyte receptor stimulation, which was reversed by the provision of exogenous Ins(1,3,4,5)P4. Our data identify Itpkb and its product Ins(1,3,4,5)P4 as inhibitors of store-operated Ca2+ channels and crucial regulators of B cell selection and activation.

Regulation of innate immunity by inositol 1,3,4,5-tetrakisphosphate

“…Miller et al, recently reported that Ins(1,3,4,5)P4 regulates B cell selection and activation via modulating store-operated calcium channels. 11 A much elevated calcium influx was detected in InsP3KB null B cells. Surprisingly, in InsP3KB null T cells, no substantial defects in Ins(1,4,5)P3 amounts or calcium mobilization was detected.…”

“…The absolute number of lymphocytes in peripheral blood was reduced significantly in the InsP3KB knockout mice. [9][10][11][12] However, intriguingly, disruption of InsP3KB resulted in elevated peripheral blood neutrophil count, indicating an augmentation of neutrophil production from bone marrow. Fluorescence-Activated Cell-sorting (FACS) analysis of bone marrow cells revealed an elevation of granulocyte monocytes progenitors (GMP) population in the knockout mice.…”

“…In addition, the amounts of mature B-and T-cells are dramatically decreased in the InsP3KB knockout mice, resulting in reduction of the serum level of IgG which is essential for opsinization and phagocytosis. [9][10][11][12] We conducted an in vitro bacteria killing assay using purified neutrophils and serum from wild-type and InsP3KB knockout mice (Fig. 2B).…”

“…9,10 Disruption of InsP3KB also induces B cell death and impaired B cell development. 11,12 In addition, we recently showed that InsP3KB is the major InsP3K isoform in neutrophils. Disruption of the single InsP3KB gene led to alteration of myelopoiesis, hyperactivation of neutrophils, and dysregulation of innate immunity.…”

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

“…TRIM family members are a class of novel ring-finger E3 ligases that have been shown to ubiquitinate a number of different proteins (30)(31)(32). To assess whether TRIM27 ubiquitinates PI3KC2β, PI3KC2β was expressed with His-tagged ubiquitin either alone or together with TRIM27 and ubiquitinated PI3KC2β was assessed following purification with Nickel (Ni)-NTA beads.…”