Phosphorylation of Acinus Regulates its Biological Functions

腺泡蛋白的磷酸化对其生物学功能的调节 摘要 腺泡(细胞核内的凋亡染色质凝聚诱导物)在细胞凋亡过程中被caspase切割，以 产生一个17 kDa的片段(P17)，在DNA片段化之前触发凋亡染色质凝聚。 AMPA诱导的兴奋性毒性增加caspase激活的腺泡的核水平并引起染色质 大鼠海马锥体神经元内凝集。腺泡位于核斑点中，包含一个 RNA识别基序(RRM)，紧随其后的是C末端的丝氨酸和富含精氨酸(SR)结构域。高度的 保守的SR蛋白是控制选择性剪接的关键分子。最近，我们展示了Akt 使腺泡磷酸化，增强其对caspase切割的抵抗力，并抑制腺泡依赖的染色质 冷凝。此外，p17片段通过启动H2B的磷酸化和染色质的缩合 激活PKC-1。我们的初步研究表明，腺泡与SRPK2结合，SRPK2是一种SR蛋白特异性激酶，它可以 使腺泡磷酸化。有趣的是，Akt还使SRPK2磷酸化。然而，这种磷酸化是否 目前尚不清楚SRPK2对神经元内腺泡蛋白降解的调节作用。此外，我们还发现PKC-？ 反馈和磷酸化腺泡，刺激其凋亡降解，但其生理意义 这种磷酸化的作用还不清楚。这些相互作用的意义和生理后果 神经元的存活仍然难以捉摸。我们假设腺泡是PKC-1和PKC-1的生理底物 SRPK2，而这些激酶的协同磷酸化将微妙地定义 神经元中的腺泡。介导腺泡磷酸化、蛋白分解的信号通路的鉴定 降解和凋亡活性不仅对于理解腺泡的生理功能是必不可少的， 而且还有上游串扰，决定了神经元中的核凋亡机制。

Phosphorylation of Acinus Regulates its Biological Functions Abstract Acinus (apoptotic chromatin condensation inducer in the nucleus) is cleaved during apoptosis by caspases to produce a 17-kDa fragment (p17), triggering apoptotic chromatin condensation prior to DNA fragmentation. AMPA-induced excitotoxicity increases nuclear levels of caspase-activated acinus and incurs chromatin condensation in rat hippocampal pyramidal neurons. Acinus localizes in the nuclear speckle and contains an RNA-recognition motif (RRM), followed by a C-terminal serine and arginine rich (SR) domain. The highly conserved SR proteins are key players in the control of alternative splicing. Recently, we showed that Akt phosphorylates acinus and enhances its resistance to caspase cleavage and inhibits acinus-dependent chromatin condensation. Moreover, the p17 fragment initiates H2B phosphorylation and chromatin condensation through activating PKC-¿. Our preliminary studies reveal that acinus binds SRPK2, an SR protein specific kinase, which phosphorylates acinus. Interestingly, Akt also phosphorylates SRPK2. However, whether this phosphorylation by SRPK2 regulates acinus proteolytic degradation in neurons remains unknown. Further, we found that PKC-¿ feeds back and phosphorylates acinus, stimulating its apoptotic degradation, but the physiological significance of this phosphorylation is unclear. The significance and physiological consequence of these interactions in neuronal survival remains elusive. We hypothesize that acinus is a physiological substrate of PKC-¿ and SRPK2, and the coordinate phosphorylation by these kinases will delicately define the physiological roles of acinus in neurons. Identification of signaling pathways mediating acinus phosphorylation, proteolytic degradation and apoptotic activity is essential for understanding not only the physiological functions of acinus, but also the upstream crosstalk dictating the nuclear apoptotic machinery in neurons.