期刊
MOLECULES AND CELLS
卷 45, 期 11, 页码 855-867出版社
KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
DOI: 10.14348/molcells.2022.0104
关键词
acetylation; ATXN3; calcium; CBP; Importin ?; nucleocytoplasmic transport
资金
- Basic Science Research Program through the National Research Foundation of Korea [2022R1A4A2000703, 2021R1A2C1003817]
- Korea Brain Research Institute (KBRI) Research Program - Ministry of Science and ICT, Republic of Korea [22-BR-03-02]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)
- Korea Dementia Research Center (KDRC) - Ministry of Health Welfare
- Ministry of Science and ICT, Republic of Korea [HU21C0027]
- National Research Foundation of Korea [2022R1A4A2000703, 2021R1A2C1003817] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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.
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