Loss of GADD34 induces early age-dependent deviation to the myeloid lineage.
Loss of GADD34 induces early age-dependent deviation to the myeloid lineage.
复制标题
GADD34 的缺失会导致早期年龄依赖性的骨髓谱系偏差。
DOI：
10.1038/icb.2013.78
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Isobe K.
中科院分区：
文献类型：
--
作者：
Nishio N;Ito S;Isobe K.
造血干细胞（HSC）产生所有已知的造血谱系，并能够自我更新。在老化时，骨髓偏向的HSC得以维持，而淋巴偏向的HSC丢失。GADD 34蛋白在髓系细胞中表达，并已从其中克隆。然而，GADD 34在髓系中的功能尚未阐明。在这里，我们表明，早期年龄依赖性偏离骨髓谱系发生在GADD 34缺陷小鼠。在GADD 34缺陷小鼠的脾脏、骨髓（BM）和血液中观察到GR-1 intCD 11b+和GR-1highCD 11b+中性粒细胞的早期增加。我们发现BM Lin−c − Kit+ Sca 1+和Lin−c − Kit+ Sca 1 −细胞在无刺激的情况下表达GADD 34蛋白，并且在静脉注射金黄色葡萄球菌（S.aureus）后GADD 34表达增加。这些细胞群在GADD 34缺陷BM中较高，并且通过注射S而增加。金黄色的由于S.金黄色葡萄球菌注射后，我们检查了来自G-CSF受体（G-CSFR）的信号通路。我们发现，在GADD 34缺陷型Lin−BM细胞中，G-CSF刺激后，信号转导和转录激活因子3的磷酸化水平显著升高。这些结果表明GADD 34结合林恩并抑制G-CSFR信号传导。我们在这里表明，GADD 34可以抑制HSC或骨髓前体细胞的增殖和分化，并维持中性粒细胞谱系细胞的稳态分化，以避免早期免疫衰老。
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‐1intCD11b+and GR‐1highCD11b+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 ofStaphylococcus aureus(S.aureus). These cell populations were high in GADD34‐deficient BM and were increased by the injection ofS. aureus. Because of the increase in granulocyte colony‐stimulating factor (G‐CSF) induced byS. aureusinjection, 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.