Acinus-provoked protein kinase C δ isoform activation is essential for apoptotic chromatin condensation
Acinus-provoked protein kinase C δ isoform activation is essential for apoptotic chromatin condensation
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DOI：
10.1038/sj.cdd.4402214
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发表时间：
2007-12-01
影响因子：
12.4
通讯作者：
Ye, K.
中科院分区：
文献类型：
--
作者：
Hu, Y.;Liu, Z.;Ye, K.
组蛋白H2 B磷酸化与细胞凋亡过程中的染色质凝聚密切相关。半胱天冬酶切割的腺泡（细胞核中的凋亡染色质凝聚诱导剂）引起细胞核中的染色质凝聚，但这种效应的分子机制仍然难以捉摸。在这里，我们报告，活性腺泡p17片段启动H2 B磷酸化和染色质凝聚通过激活蛋白激酶C6亚型（PKC-δ）。我们发现p17与Mst 1和150-delta结合，后者受到细胞凋亡刺激的上调，从而增强了它们的激酶活性。与野生型相比，易降解的腺泡突变体具有更强的染色质凝聚和更高的H2 B磷酸化。显性负性PKC-δ而不是Mst 1强烈阻断腺泡启动的H2 B磷酸化。令人惊讶的是，Mst 1的缺失触发caspase-3激活，通过激活PKC-δ引起H2 B磷酸化。此外，在PKC-δ缺陷的小鼠胚胎成纤维细胞和siRNA敲低的PC 12细胞中，腺泡引起的H2 B磷酸化和染色质浓缩被废除。因此，PKC-δ而不是Mst 1作为一个生理下游激酶的腺泡在促进H2 B磷酸化和染色质凝聚。
Histone H2B phosphorylation tightly correlates with chromatin condensation during apoptosis. The caspase-cleaved acinus (apoptotic chromatin condensation inducer in the nucleus) provokes chromatin condensation in the nucleus, but the molecular mechanism accounting for this effect remains elusive. Here, we report that the active acinus p17 fragment initiates H2B phosphorylation and chromatin condensation by activating protein kinase C 6 isoform (PKC-delta). We show that p17 binds to both Mst1 and 150-delta, which is upregulated by apoptotic stimuli, enhancing their kinase activities. Acinus mutant susceptible to degradation elicits stronger chromatin condensation and higher H2B phosphorylation than wild-type acinus. Dominant-negative PKC-delta but not Mst1 robustly blocks acinus-initiated H2B phosphorylation. Surprisingly, depletion of Mst1 triggers caspase-3 activation, provoking H2B phosphorylation through activating PKC-delta. Further, acinus-elicited H2B phosphorylation and chromatin condensation are abrogated in PKC-delta-deficient mouse embryonic fibroblast cells and siRNA-knocked down PC12 cells. Thus, PKC-delta but not Mst1 acts as a physiological downstream kinase of acinus in promoting H2B phosphorylation and chromatin condensation.