| ○種別 (必須): | □ | 学術論文 (審査論文)
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| ○言語 (必須): | □ | 英語
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| ○招待 (推奨): |
| ○審査 (推奨): | □ | Peer Review
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| ○カテゴリ (推奨): | □ | 研究
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| ○共著種別 (推奨): | □ | 単独著作 (徳島大学内の単一の研究グループ(研究室等)内の研究 (単著も含む))
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| ○学究種別 (推奨): | □ | 博士課程学生による研究報告
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| ○組織 (推奨): |
| ○著者 (必須): | 1. | (英) Shiro Yuki (日) 城 裕己 (読) しろ ゆうき
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| ○学籍番号 (推奨): | □ | ****
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| 2. | 片山 将一 ([徳島大学.大学院医歯薬学研究部.薬学域.先端薬学教育研究プロジェクト]/[徳島大学.大学院医歯薬学研究部.薬学域.薬科学部門.生命薬学系.医薬品病態生化学])
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| 3. | (英) Tsukamoto Haruka (日) 塚本 陽花 (読) つかもと はるか
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| ○学籍番号 (推奨): | □ | ****
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| 4. | 山﨑 哲男 ([徳島大学.大学院医歯薬学研究部.薬学域.薬科学部門.生命薬学系.医薬品病態生化学])
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| ○題名 (必須): | □ | (英) Pro-cathepsin D prevents aberrant protein aggregation dependent on endoplasmic reticulum protein CLN6. (日)
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| ○要約 (任意): | □ | (英) We previously expressed a chimeric protein in which the small heat-shock protein αB-crystallin (αBC) 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 αBC was shown to prevent the aggregation of the coexpressed R120G αBC variant, which is highly aggregation-prone and associated with the hereditary myopathy αB-crystallinopathy. To uncover a molecular mechanism by which the ER-anchored αBC negatively regulates the protein aggregation, we isolated proteins that bind to the ER-anchored αBC 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 αBC 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 αBC 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 αBC, prevents the R120G αBC 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. (日)
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| ○キーワード (推奨): |
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| ○誌名 (必須): | □ | Molecular Genetics and Metabolism (Society for Inherited Metabolic Disorders)
(pISSN: 1096-7192, eISSN: 1096-7206)
| ○ISSN (任意): | □ | 1096-7206
ISSN: 1096-7192
(pISSN: 1096-7192, eISSN: 1096-7206) Title: Molecular genetics and metabolismTitle(ISO): Mol Genet MetabPublisher: Academic Press Inc. (NLM Catalog)
(Scopus)
(CrossRef)
(Scopus information is found. [need login]) | [継承] |
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| ○巻 (必須): | □ | 143
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| ○号 (必須): | □ | 1-2
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| ○頁 (必須): | □ | 108539 108539
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| ○都市 (任意): |
| ○年月日 (必須): | □ | 西暦 2024年 7月 16日 (令和 6年 7月 16日)
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| ○URL (任意): |
| ○DOI (任意): | □ | 10.1016/j.ymgme.2024.108539 (→Scopusで検索)
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| ○PMID (任意): | □ | 39032464 (→Scopusで検索)
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| ○指導教員 (推奨): | 1. | 山﨑 哲男 ([徳島大学.大学院医歯薬学研究部.薬学域.薬科学部門.生命薬学系.医薬品病態生化学])
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| ○備考 (任意): | 1. | (英) PublicationType: Journal Article (日)
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