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

Abstract

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 α3 (Imp α3). 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 α3 to regulate NCT of ATXN3. These findings demonstrate that CBP-dependent acetylation of Imp α3 is crucial for intracellular calciumdependent NCT of ATXN3 proteins, different from that of TDP-43, in Drosophila neurons.

Drosophila Importin Alpha 1 (Dα1) Is Required to Maintain Germline Stem Cells in the Testis Niche

“…A study that utilised pharmacological inhibitors of importin activity was able to prevent nuclear importation of pathological Tau proteins and inhibit the cell death that is associated with their expression [ 42 ]. In a similar manner, genetic experiments in Drosophila have shown that Dα3 is required for the transportation of a pathogenic truncated Ataxin-3 variant protein into nuclei, which then results in neuronal toxicity [ 43 ].…”

A comparison study of pathological features and drug efficacy between Drosophila models of C9orf72 ALS/FTD

“…As previously described by Cho et al, 2022 , Park et al, 2020 , Ryu et al, 2022 , adult flies were dissected in Schneider's insect medium (Cat No. S0146; Sigma) to obtain brain samples for immunohistochemical analysis.…”

Unveiling the complexity: assessing models describing the structure and function of the nuclear pore complex

“…Calcium has been shown to play a role in regulating the size and shape of the NPC ( Moore-Nichols et al, 2002 ; Erickson et al, 2006 ); however, it is not clear whether or not this action has a significant impact on transport through the pore ( Sarma and Yang, 2011 ). Cho et al, investigating the regulation of the nucleocytoplasmic transport of truncated ataxin-3 (ATXN3) proteins in Drosophila neurons, found that decreasing intracellular calcium levels can reduce the nuclear accumulation of ATXN3; however, this is likely a result of calcium-mediated regulation of CBP rather than the constriction of the pore ( Cho et al, 2022 ).…”