Loss of GADD34 induces early age‐dependent deviation to the myeloid lineage

Hematopoietic stem cells (HSCs) generate all known hematopoietic lineages and are capable of self‐renewal. Upon aging, myeloid‐biased HSCs are maintained, whereas lymphoid‐biased HSCs are lost. GADD34 protein is expressed in myeloid‐lineage cells and has been cloned from them. However, the function of GADD34 in the myeloid lineage has not yet been elucidated. Here, we show that early age‐dependent deviation to the myeloid lineage occurs in GADD34‐deficient mice. Early increases of GR‐1 int CD11b + and GR‐1 high CD11b + neutrophils were observed in the spleen, bone marrow (BM) and blood of GADD34‐deficient mice. We found that BM Lin − c‐Kit + Sca1 + and Lin − c‐Kit + Sca1 − cells expressed GADD34 protein without stimulation and increased GADD34 expression following intravenous injection of Staphylococcus aureus ( S.aureus ). These cell populations were high in GADD34‐deficient BM and were increased by the injection of S. aureus . Because of the increase in granulocyte colony‐stimulating factor (G‐CSF) induced by S. aureus injection, we examined the signaling pathway from the G‐CSF receptor (G‐CSFR). We found that phosphorylation of signal transducer and activator of transcription factor 3 was highly increased in GADD34‐deficient Lin − BM cells by the stimulation of G‐CSF. These results indicate that GADD34 binds to Lyn and inhibit G‐CSFR signaling. We show here that GADD34 works to inhibit the proliferation and differentiation of HSCs or myeloid precursor cells and maintains homeostatic differentiation of neutrophil‐lineage cells to avoid early immunological senescence.