ID | 119515 |
著者 |
Shiro, Yuki
Tokushima University
Tsukamoto, Haruka
Tokushima University
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キーワード | Cathepsin D
Pro-cathepsin D
CLN6
Neuronal ceroid Lipofuscinosis
Alzheimer's disease
Pro-peptide
Endoplasmic reticulum
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資料タイプ |
学術雑誌論文
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抄録 | We previously expressed a chimeric protein in which the small heat-shock protein aB-crystallin (aBC) is fused at its N-terminus to the C-terminus of the first transmembrane segment of the endoplasmic reticulum (ER) protein mitsugumin 23 and confirmed its localization to the ER. Moreover, overexpression of this N-terminally modified aBC was shown to prevent the aggregation of the coexpressed R120G aBC variant, which is highly aggregation-prone and associated with the hereditary myopathy aB-crystallinopathy. To uncover a molecular mechanism by which the ER-anchored aBC negatively regulates the protein aggregation, we isolated proteins that bind to the ER-anchored aBC and identified the lysosomal protease cathepsin D (CTSD) as one such interacting protein. Proteolytically active CTSD is produced by multi-step processing of pro-cathepsin D (proCTSD), which is initially synthesized in the ER and delivered to lysosomes. When overexpressed, CTSD itself prevented the coexpressed R120G aBC variant from aggregating. This anti-aggregate activity was also elicited upon overexpression of the W383C CTSD variant, which is predominantly sequestered in the ER and consequently remains unprocessed, suggesting that proCTSD, rather than mature CTSD, serves to suppress the aggregation of the R120G aBC variant. Meanwhile, overexpression of the A58V CTSD variant, which is identical to wild-type CTSD except for the Ala58Val substitution within the pro-peptide, did not suppress the protein aggregation, indicating that the integrity of the pro-peptide is required for proCTSD to exert its anti-aggregate activity. Based on our previous finding that overexpression of the ER transmembrane protein CLN6 (ceroid-lipofuscinosis, neuronal 6), identified as an interacting protein of the ER-anchored aBC, prevents the R120G aBC variant from aggregating, the CLN6-proCTSD coupling was hypothesized to underpin the functionality of proCTSD within the ER. Indeed, CTSD, when overexpressed in CLN6-depleted cells, was unable to exert its anti-aggregate activity, supporting our view. Collectively, we show here that proCTSD prevents the protein aggregation through the functional association with CLN6 in the microenvironment surrounding the ER membrane, shedding light on a novel aspect of proCTSD and its potential involvement in CTSD-related disorders characterized by the accumulation of aberrant protein aggregates.
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掲載誌名 |
Molecular Genetics and Metabolism
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ISSN | 10967206
10967192
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cat書誌ID | AA11535388
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出版者 | AA11158931
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巻 | 143
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号 | 1-2
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開始ページ | 108539
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発行日 | 2024-07-16
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備考 | 論文本文は2025-07-16以降公開予定
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権利情報 | © 2024. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
https://creativecommons.org/licenses/by-nc-nd/4.0/ |
EDB ID | |
出版社版DOI | |
出版社版URL | |
言語 |
eng
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著者版フラグ |
その他
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部局 |
薬学系
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