CBP-Mediated Acetylation of Importin α Mediates Calcium-Dependent Nucleocytoplasmic Transport of Selective Proteins in Drosophila Neurons

For proper function of proteins, their subcellular localization needs to be monitored and regulated in response to the changes in cellular demands. In this regard, dysregulation in the nucleocytoplasmic transport (NCT) of proteins is closely associated with the pathogenesis of various neurodegenerative diseases. However, it remains unclear whether there exists an intrinsic regulatory pathway(s) that controls NCT of proteins either in a commonly shared manner or in a target-selectively different manner. To dissect between these possibilities, in the current study, we investigated the molecular mechanism regulating NCT of truncated ataxin-3 (ATXN3) proteins of which genetic mutation leads to a type of polyglutamine (polyQ) diseases, in comparison with that of TDP-43. In Drosophila dendritic arborization (da) neurons, we observed dynamic changes in the subcellular localization of truncated ATXN3 proteins between the nucleus and the cytosol during development. Moreover, ectopic neuronal toxicity was induced by truncated ATXN3 proteins upon their nuclear accumulation. Consistent with a previous study showing intracellular calcium-dependent NCT of TDP-43, NCT of ATXN3 was also regulated by intracellular calcium level and involves Importin alpha 3 (Imp alpha 3). Interestingly, NCT of ATXN3, but not TDP-43, was primarily mediated by CBP. We further showed that acetyltransferase activity of CBP is important for NCT of ATXN3, which may acetylate Imp alpha 3 to regulate NCT of ATXN3. These findings demonstrate that CBP-dependent acetylation of Imp alpha 3 is crucial for intracellular calcium-dependent NCT of ATXN3 proteins, different from that of TDP-43, in Drosophila neurons.

Automated summary

Proper regulation of nucleocytoplasmic transport (NCT) is essential for protein function, and dysregulation of NCT is associated with neurodegenerative diseases. In this study, the molecular mechanism of NCT of truncated ATXN3 proteins in comparison with TDP-43 was investigated. The results show that NCT of ATXN3 is regulated by intracellular calcium level and involves Importin alpha 3 (Imp alpha 3), primarily mediated by CBP. Acetyltransferase activity of CBP is important for NCT of ATXN3, which may acetylate Imp alpha 3 to regulate NCT of ATXN3.