Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice
Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice
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DOI：
10.1016/j.cell.2007.10.035
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发表时间：
2007-12-14
期刊：
影响因子：
64.5
通讯作者：
Tanaka, Keiji
中科院分区：
文献类型：
--
作者：
Komatsu, Masaaki;Waguri, Satoshi;Tanaka, Keiji
组成性自噬的失活导致细胞质蛋白包涵体的形成，并导致肝损伤和神经变性，但与受损的自噬相关的异常的细节在很大程度上是未知的。在这里，我们使用小鼠遗传分析来定义自噬在上述事件中的作用。据报道，泛素和LC 3结合蛋白“p62”调节蛋白质聚集体的形成，并通过自噬被去除。因此，基因消融p62抑制了肝细胞和神经元中泛素阳性蛋白聚集体的出现，表明p62在包涵体形成中起着重要作用。此外，p62的损失显着减弱自噬缺陷引起的肝损伤，而它对神经元变性几乎没有影响。我们的研究结果突出了意想不到的作用，稳态水平的p62，这是由自噬调节，在控制细胞内包涵体的形成，并表明与自噬缺陷的病理过程是细胞类型特异性。
Inactivation of constitutive autophagy results in formation of cytoplasmic protein inclusions and leads to liver injury and neurodegeneration, but the details of abnormalities related to impaired autophagy are largely unknown. Here we used mouse genetic analyses to define the roles of autophagy in the aforementioned events. Were-port that the ubiquitin-and LC3-binding protein "p62'' regulates the formation of protein aggregates and is removed by autophagy. Thus, genetic ablation of p62 suppressed the appearance of ubiquitin-positive protein aggregates in hepatocytes and neurons, indicating that p62 plays an important role in inclusion body formation. Moreover, loss of p62 markedly attenuated liver injury caused by autophagy deficiency, whereas it had little effect on neuronal degeneration. Our findings highlight the unexpected role of homeostatic level of p62, which is regulated by autophagy, in controlling intracellular inclusion body formation, and indicate that the pathologic process associated with autophagic deficiency is cell-type specific.