Eukaryotic initiation factor 2α phosphorylation is required for B-cell maturation and function in mice

Background The control of translation initiation is a crucial component in the regulation of gene expression. The eukaryotic initiation factor 2 alpha (eIF2 alpha) mediates binding of the initiator transfer-messenger-RNA to the AUG initiation codon, and thus controls a rate-limiting step in translation initiation. Phosphorylation of eIF2 alpha at serine 51 is linked to cellular stress response and attenuates translation initiation. The biochemistry of translation inhibition mediated by eIF2 alpha phosphorylation is well characterized, yet the physiological importance in hematopoiesis remains only partially known. Design and Methods Using hematopoietic stem cells carrying a non-phosphorylatable mutant form of eIF2 alpha (eIF2 alpha AA), we examined the efficiency of reconstitution in wild-type and B-cell-deficient microMT C57BL/6 recipients in two independent models. Results We provide evidence that phosphorylation-deficient eIF2 alpha mutant hematopoietic stem cells may repopulate lethally irradiated mice but have a defect in the development and maintenance of newly formed B cells in the bone marrow and of naive follicular B cells in the periphery. The mature B-cell compartment is markedly reduced in bone marrow, spleen and peripheral blood, and B-cell receptor-mediated proliferation in vitro and serum immunoglobulin secretion in vivo are impaired. Conclusions The data suggest that regulation of translation through eIF2 alpha phosphorylation is dispensable in hematopoietic reconstitution but essential during late B-cell development.