Phosphorylation of Acinus Regulates its Biological Functions

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DESCRIPTION (provided by applicant): 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-4. 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-4 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-4 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. PUBLIC HEALTH RELEVANCE: Acinus localizes in the specific nuclear compartment, called nuclear speckles, mediating cell survival and RNA processing. Acinus induces chromatin condensation after its cleavage by caspases, which are the enzymes responsible for cutting many cellular proteins. We found that protein kinase Akt, a critical kinase for cell survival and many other cellular functions, phosphorylates acinus, prevents its degradation by caspases, and suppresses chromatin condensation, a process associated with programmed cell death. In our preliminary studies, we also found that protein kinases including PKC-4 and SRPK2 phosphorylate acinus and modulate its degradation, a process activating acinus. However, whether the phosphorylation by PKC-4 and SRPK2 plays any role in regulating acinus proteolytic degradation in neurons remains unknown. Further, how these upstream kinases communicate with each other to orchestrate the signaling is unclear. Here, we propose experiments to test the hypothesis that acinus is a physiological substrate of PKC-4 and SRPK2, and the coordinate phosphorylation by these kinases will delicately define the physiological roles of acinus in neurons. To characterize signaling pathways mediating acinus phosphorylation, proteolytic degradation and programmed cell death activity is essential for understanding not only the physiological functions of acinus, but also the upstream crosstalk dictating the nuclear apoptotic machinery in neurons. This will pave the way for the identification of novel drug targets for the treatment of patients with neurodegenerative diseases.