PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development.
PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development.
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DOI：
10.1038/emboj.2013.40
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发表时间：
2013-04-03
期刊：
影响因子：
11.4
通讯作者：
Arthur, J. Simon C.
中科院分区：
文献类型：
--
作者：
Venigalla, Ram K. C.;McGuire, Victoria A.;Clarke, Rosemary;Patterson-Kane, Janet C.;Najafov, Ayaz;Toth, Rachel;McCarthy, Pierre C.;Simeons, Frederick;Stojanovski, Laste;Arthur, J. Simon C.
磷酸肌苷依赖性激酶-1 （PDK1）控制AGC激酶子集的激活。通过在造血细胞中有条件地敲除PDK1，我们证明了PDK1对B细胞的发育至关重要。由于细胞自主缺陷，缺乏PDK1的b细胞祖细胞在前b细胞向前b细胞过渡时受阻。由于IgH远端可变片段的重组受损，PDK1的缺失降低了亲b细胞中IgH链的表达，这一过程由转录因子Pax5协调。PDK1敲除后，前b细胞中Pax5的表达降低，这与Pax5靶基因IRF4、IRF8和Aiolos的表达降低有关。因此，Ccnd3在PDK1敲除前b细胞中上调，并且它们经历细胞周期阻滞的能力受损，这是Ig轻链重排的必要事件。相反，这些细胞发生凋亡，与促生存基因Bcl2A1的表达减少有关。将Pax5和Bcl2A1一起重新引入PDK1敲除前B细胞中，恢复了它们在体外向成熟B细胞分化的能力。
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.
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