MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, UK.
EMBO J. 2013 Apr 3;32(7):1008-22. doi: 10.1038/emboj.2013.40. Epub 2013 Mar 5.
Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells.
磷酸肌醇依赖激酶-1（PDK1）控制着一组 AGC 激酶的激活。通过对造血细胞中 PDK1 的条件性敲除，我们证明 PDK1 对 B 细胞的发育是必不可少的。由于细胞自主缺陷，缺乏 PDK1 的 B 细胞前体在从前 B 细胞到 pre-B 细胞的过渡中停滞不前。由于 IgH 远端可变片段的重组受损，PDK1 的缺失降低了 pro-B 细胞中 IgH 链的表达，这一过程由转录因子 Pax5 协调。PDK1 敲除的 pre-B 细胞中 Pax5 的表达减少，这与 Pax5 靶基因 IRF4、IRF8 和 Aiolos 的表达减少相关。结果，Ccnd3 在 PDK1 敲除的 pre-B 细胞中上调，它们进行细胞周期阻滞的能力受损，这是 Ig 轻链重排所必需的事件。相反，这些细胞发生了凋亡，这与抗凋亡基因 Bcl2A1 的表达减少相关。将 Pax5 和 Bcl2A1 一起重新导入 PDK1 敲除的 pro-B 细胞中，恢复了它们在体外分化为成熟 B 细胞的能力。
