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 tmRNA to the AUG initiation codon, and thus controls a rate-limiting step in translation initiation. Phosphorylation of eIF2{alpha} at serine 51 (S51) 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 S51A mutant form of eIF2{alpha} (eIF2{alpha}AA), we examined the efficiency of reconstitution in wildtype (WT) or B cell-deficient microMT({mu}MT) C57BL/6 recipients in two independent models. Results. We provide evidence that phosphorylation-deficient S51A 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 naïve follicular B (FOB) cells in the periphery. The mature B cell compartment is markedly reduced in bone marrow, spleen and peripheral blood, and B cell receptor (BCR)-mediated proliferation in vitro and serum immunoglobulin (Ig) 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.