Age-related decline in chaperone-mediated autophagy
Age-related decline in chaperone-mediated autophagy
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DOI：
10.1074/jbc.m002102200
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发表时间：
2000-10-06
影响因子：
4.8
通讯作者：
Dice, JF
中科院分区：
文献类型：
--
作者：
Cuervo, AM;Dice, JF
在许多组织和器官中，细胞内蛋白质降解速率随着年龄的增长而降低。在培养的细胞中，负责选择性降解溶酶体中胞质蛋白的分子伴侣介导的自噬随着年龄的增长而减少。在这项工作中，我们使用从大鼠肝脏中分离的溶酶体来分析与年龄相关的伴侣介导的自噬的主要成分的水平和活动的变化。来自“老”（22个月大）大鼠的溶酶体显示出较低的伴侣蛋白介导的自噬率，并且底物与溶酶体膜的结合和向溶酶体的转运都随着年龄的增长而下降。作为伴侣介导的自噬的受体的溶酶体相关膜蛋白2a型的水平的逐渐的年龄相关的减少是负责在老年大鼠的溶酶体中的底物结合减少，以及从晚期传代的人成纤维细胞。底物靶向溶酶体所需的73 kDa热休克同源蛋白的胞质水平和活性随年龄变化。溶酶体相关hsc73的水平仅在年龄最大的大鼠中增加。这种增加可能是为了补偿随着年龄的增长而减少的通路活性。
Intracellular protein degradation rates decrease with age in many tissues and organs. In cultured cells, chaperone-mediated autophagy, which is responsible for the selective degradation of cytosolic proteins in lysosomes, decreases with age. In this work we use lysosomes isolated from rat liver to analyze age-related changes in the levels and activities of the main components of chaperone-mediated autophagy. Lysosomes from "old" (22-month-old) rats show lower rates of chaperone-mediated autophagy, and both substrate binding to the lysosomal membrane and transport into lysosomes decline with age. A progressive age-related decrease in the levels of the lysosome-associated membrane protein type 2a that acts as a receptor for chaperone-mediated autophagy was responsible for decreased substrate binding in lysosomes from old rats as well as from late passage human fibroblasts. The cytosolic levels and activity of the 73-kDa heat-shock cognate protein required for substrate targeting to lysosomes were unchanged with age. The levels of lysosome-associated hsc73 were increased only in the oldest rats. This increase may be an attempt to compensate for reduced activity of the pathway with age.