Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging.
Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging.
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DOI：
10.1111/acel.12777
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发表时间：
2018-08
期刊：
影响因子：
7.8
通讯作者：
Cuervo AM
中科院分区：
文献类型：
--
作者：
Bejarano E;Murray JW;Wang X;Pampliega O;Yin D;Patel B;Yuste A;Wolkoff AW;Cuervo AM
随着年龄的增长而不能保持蛋白质平衡有助于逐渐丧失功能，这是老年生物体的特征。有缺陷的自噬是溶酶体中细胞内物质传递和降解的蛋白质静止网络的一个组成部分，已在多种老年生物体中被描述，而强大的自噬反应与长寿有关。随着年龄的增长，导致自噬功能缺陷的分子机制在很大程度上仍然没有得到很好的描述。在这项工作中，我们已经确定了年轻细胞和老年细胞在参与自噬的囊泡室的细胞内运输中的差异。随着年龄的增长，自噬体和溶酶体不能重新定位到核周区域，降低了它们融合的效率和随后被隔离的货物的降解。老年小鼠肝细胞显示，两种基于微管的负端定向运动蛋白（已被充分表征的动力蛋白和较少研究的KIFC3）分别与自噬体和溶酶体的关联较低。利用遗传学方法模拟在老年细胞中观察到的较低水平的KIFC3，我们证实了成纤维细胞中这种运动蛋白含量的降低导致溶酶体重新定位失败和自噬通量减少。我们的研究将老年生物细胞内运输缺陷与自噬不足联系起来，并确定了运动蛋白作为未来干预的新靶点，旨在通过抗衰老的目的纠正自噬活性。
Inability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule‐based minus‐end‐directed motor proteins, the well‐characterized dynein, and the less‐studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti‐aging purposes.
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影响因子：
13.3
作者：
Katsumata, Kiyoshi;Nishiyama, Jun;Yuzaki, Michisuke
通讯作者：
Yuzaki, Michisuke
影响因子：
82.9
作者：
Kaushik, Susmita;Cuervo, Ana Maria
通讯作者：
Cuervo, Ana Maria
DOI：
10.1093/gerona/56.9.b375
发表时间：
2001-09-01
影响因子：
5.1
作者：
Donati, A;Cavallini, G;Bergamini, E
通讯作者：
Bergamini, E
影响因子：
56.9
作者：
IVY, GO;SCHOTTLER, F;LYNCH, G
通讯作者：
LYNCH, G
影响因子：
11.4
作者：
Cuervo, Ana Maria
通讯作者：
Cuervo, Ana Maria