Protein Kinase CK2 Drives Plasma Cell Differentiation

Abstract

Abstract Casein kinase 2 (CK2) is a serine/threonine protein kinase composed of three subunits: two catalytic subunits, CK2α and CK2α’, and the regulatory subunit CK2β. It is overexpressed and overactive in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphomas, leading to inappropriate activation of NF-κB, JAK/STAT and PI3K/AKT/mTOR signaling, but little is known about how CK2 functions in normal B-cell differentiation. Here, we demonstrate that CK2 mRNA and protein expression is induced upon B-cell activation. Using the small molecule inhibitor CX-4945, which targets the catalytic activity of CK2, a significant inhibition of plasma cell differentiation was observed in vitro under T-cell-independent (TI) or T-cell-dependent (TD) conditions via stimulation with lipopolysaccharide (LPS) or CD40L and interleukin 4 (IL-4) +IL-5, respectively. At the cellular level, we found that inhibition of CK2 kinase activity in B-cells resulted in defective mTORC1 signaling upon stimulation with LPS. These results were confirmed in purified mature B-cells from mice with tamoxifen-induced global deletion of CK2α. These data demonstrate that CK2α is an important regulator of B-cell differentiation. Ongoing experiments with B-cell specific deletion of CK2α will further examine the impact of CK2α on B-cell differentiation in vivo.