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

因为已知的溶酶体降解途径不能完全解释细胞中溶酶体蛋白分解的总水平(童等人。2020)和蛋白质在细胞中的积累是神经退行性疾病的标志，我们在溶酶体中寻找新的蛋白质降解途径。我们发现，胞浆蛋白通过一种不同于任何已知途径的直接摄取机制进入溶酶体，然后被降解。SIDT2在组成水平(营养丰富的条件下)介导细胞内多种胞质蛋白的溶酶体降解，并对其易位起重要作用。我们还发现了SIDT2基因的一个显性-负性突变，该突变导致人类家族性神经病和远端有空泡的肌病，并证实了SIDT2基因敲除小鼠概括了这种疾病的典型特征。这些结果揭示了溶酶体中蛋白质分解的未知途径，并强调了蛋白质溶酶体降解在人类生理学和病理生理学中的重要性。

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.