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ID 119515
著者
Shiro, Yuki Tokushima University
Tsukamoto, Haruka Tokushima University
キーワード
Cathepsin D
Pro-cathepsin D
CLN6
Neuronal ceroid Lipofuscinosis
Alzheimer's disease
Pro-peptide
Endoplasmic reticulum
資料タイプ
学術雑誌論文
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.
掲載誌名
Molecular Genetics and Metabolism
ISSN
10967206
10967192
cat書誌ID
AA11535388
出版者
AA11158931
143
1-2
開始ページ
108539
発行日
2024-07-16
備考
論文本文は2025-07-16以降公開予定
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
著者版フラグ
その他
部局
薬学系