p62-and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome
p62-and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome
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DOI：
10.1073/pnas.1615455113
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发表时间：
2016-11-22
影响因子：
11.1
通讯作者：
Ciechanover, Aaron
中科院分区：
文献类型：
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作者：
Cohen-Kaplan, Victoria;Livneh, Ido;Ciechanover, Aaron
泛素-蛋白酶体系统和自噬是两种主要的蛋白水解系统，其参与通过消除错误折叠和受损的蛋白质和细胞器来维持细胞完整性。这两种系统在与泛素缀合后都去除了它们的靶标。一个有趣但尚未完全理解的问题与这两个系统的组成部分的命运有关。在这里，我们提供的证据表明，氨基酸饥饿增强了蛋白酶体的特定位点上的多聚泛素化，这是一种对其靶向自噬机制至关重要的修饰。泛素化蛋白酶体的摄取是通过其与p62/SQSTM 1的泛素相关结构域的相互作用介导的，这一过程也需要与LC 3相互作用。重要的是，p62的PB 1结构域的缺失，这是重要的靶向泛素化底物的蛋白酶体，有没有影响应激诱导的自噬这种蛋白水解机制，这表明结合到蛋白酶体的p62的结构域决定的功能p62在靶向底物的蛋白酶体或靶向蛋白酶体自噬。
The ubiquitin-proteasome system and autophagy are the two main proteolytic systems involved in, among other functions, the maintenance of cell integrity by eliminating misfolded and damaged proteins and organelles. Both systems remove their targets after their conjugation with ubiquitin. An interesting, yet incompletely understood problem relates to the fate of the components of the two systems. Here we provide evidence that amino acid starvation enhances polyubiquitination on specific sites of the proteasome, a modification essential for its targeting to the autophagic machinery. The uptake of the ubiquitinated proteasome is mediated by its interaction with the ubiquitin-associated domain of p62/SQSTM1, a process that also requires interaction with LC3. Importantly, deletion of the PB1 domain of p62, which is important for the targeting of ubiquitinated substrates to the proteasome, has no effect on stress-induced autophagy of this proteolytic machinery, suggesting that the domain of p62 that binds to the proteasome determines the function of p62 in either targeting substrates to the proteasome or targeting the proteasome to autophagy.