Phosphorylation of Acinus Regulates its Biological Functions

Emory University, Atlanta GA

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Abstract

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.