Selective turnover of p62/A170/SQSTM1 by autophagy
Selective turnover of p62/A170/SQSTM1 by autophagy
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DOI：
10.4161/auto.6826
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发表时间：
2008-11-16
期刊：
影响因子：
13.3
通讯作者：
Komatsu, Masaaki
中科院分区：
文献类型：
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作者：
Ichimura, Yoshinobu;Kominami, Eiki;Komatsu, Masaaki
自噬的丧失导致肝损伤、心肌病和神经变性，与泛素阳性包涵体的形成相关。然而，致病机制和参与包涵体形成的分子机制尚未完全了解。我们最近发现了一个泛素结合蛋白p62/A170/SQSTM 1，作为一个参与包涵体形成的分子。p62通过富含酸性和疏水性残基的氨基酸序列（称为LC 3-识别序列（LRS））与调节自噬体形成的LC 3相互作用，并且LC 3-p62复合物被自噬降解。此外，结构分析揭示了Trp-340和Leu-343的p62与LC 3的泛素折叠中的不同疏水口袋的相互作用。p62突变体，在结合LRS的缺陷，逃避有效的周转自噬，形成泛素和p62阳性夹杂物。重要的是，这种泛素和p62阳性包涵体在各种人类疾病中被鉴定，这意味着自噬参与其致病机制。我们的报告确定了自噬在P62的选择性周转中的重要作用，并证明了除了LC 3在自噬体形成中的重要作用外，LC 3还参与了自噬特异性底物的分选。
Loss of autophagy causes liver injury, cardiomyopathy and neurodegeneration, associated with the formation of ubiquitin-positive inclusion bodies. However, the pathogenic mechanism and molecular machinery involved in inclusion formation are not fully understood. We recently identified a ubiquitin -binding protein, p62/A170/SQSTM1, as a molecule involved in inclusion formation. p62 interacts with LC3 which regulates autophagosome formation, through a-n I I amino acid sequence rich in acidic and hydrophobic residues, named the LC3-recognition sequence (LRS), and the LC3-p62 complex is degraded by autophagy. Furthermore, structural analysis reveals an interaction of Trp-340 and Leu-343 of p62 with different hydrophobic pockets in the ubiquitin-fold of LC3. p62 mutants, defective in binding the LRS, escape efficient turnover by autophagy, forming ubiquitin- and p62-positive inclusions. Importantly, such ubiquitin- and p62-positive inclusions are identified in various human diseases, implying the involvement of autophagy in their pathogenic mechanisms. Our reports identify an important role for autophagy in the selective turnover of P62, and demonstrate that in addition to the essential role of LC3 in autophagosome formation, LC3 is also involved in sorting autophagy-specific substrate(s).