核酸を分解する膜透過型オートファジーのメカニズムと疾患との関連

跨膜自噬降解核酸的机制及其与疾病的关系

• 批准号: 18F18384
• 负责人: 株田 智弘
• 金额: $ 1.41万
• 依托单位: National Center of Neurology and Psychiatry
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2018
• 资助国家: 日本
• 起止时间: 2018-11-09 至 2021-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18F18384/
• 关键词: autophagy; Autophagy; neurodegeneration; RNautophagy; lysosome; SIDT2; lysosomal degradation

Because already known lysosomal degradation pathways cannot fully account for total levels of lysosomal proteolysis in cells (Tong et al. 2020) and protein accumulation in cells is a hallmark of neurodegenerative diseases, we sought for novel protein degradation pathways in lysosomes.We found that cytosolic proteins are imported into lysosomes by a direct uptake mechanism which is distinct from any known pathways, and then degraded. SIDT2 mediates the translocation and contributes conspicuously to the lysosomal degradation of a wide range of cytosolic proteins in cells at the constitutive level (nutrient-rich condition). We also identified a dominant-negative mutation in SIDT2 which causes familial neuropathy and distal myopathy with rimmed vacuoles in humans and confirmed that Sidt2 knockout mice recapitulate the typical features of the disease.These results reveal previously unknown pathway of proteolysis in lysosomes and highlight the importance of lysosomal degradation of proteins in human physiology and pathophysiology.

由于已知的溶酶体降解途径无法完全解释细胞中溶酶体蛋白水解的总水平（Tong et al. 2020），并且细胞中蛋白质积累是神经退行性疾病的标志，因此我们在溶酶体中寻找新的蛋白质降解途径。我们发现胞质蛋白通过直接摄取机制导入溶酶体，该机制不同于任何已知途径， 然后退化。 SIDT2 介导易位，并显着促进细胞中多种胞质蛋白在组成水平（营养丰富的条件）的溶酶体降解。我们还发现了 SIDT2 的显性失活突变，该突变会导致人类家族性神经病和带有边缘空泡的远端肌病，并证实 Sidt2 敲除小鼠重现了该疾病的典型特征。这些结果揭示了以前未知的溶酶体蛋白水解途径，并强调了溶酶体蛋白降解在人类生理学和免疫学中的重要性。 病理生理学。

项目成果

RNautophagy: mediators and mechanisms at the cellular level

RN自噬：细胞水平的介质和机制

• 发表时间: 2019
• 作者: Viorica Raluca Contu;Katsunori Hase;Chihana Kabuta;Yuuki Fujiwara;Keiji Wada;Tomohiro Kabuta.
• 通讯作者: Tomohiro Kabuta.

Cytosolic domain of SIDT2 carries an arginine-rich motif that binds to RNA/DNA and is important for the direct transport of nucleic acids into lysosomes

• DOI: 10.1080/15548627.2020.1712109
• 发表时间: 2020-01-18
• 期刊: AUTOPHAGY
• 影响因子: 13.3
• 作者: Hase, Katsunori;Contu, Viorica Raluca;Kabuta, Tomohiro
• 通讯作者: Kabuta, Tomohiro