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标题：p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome
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作者：Victoria Cohen-Kaplan ; Ido Livneh ; Noa Avni 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：47
页码：E7490-E7499
DOI：10.1073/pnas.1615455113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWhereas the role of the ubiquitin system in protein degradation is well established, little is known regarding the regulation of its own components, including its catalytic arm, the 26S proteasome. Here we show that in stressed mammalian cells, the proteasome is targeted by autophagy, which requires site-specific ubiquitination of its ubiquitin receptors. The process is mediated by the p62/SQSTM1 adapter and requires its ubiquitin-associated domain. Independently, p62 serves also as a shuttling protein for ubiquitinated substrates, using its PB1 domain. This places p62 in a pivotal position where under certain conditions it binds to the proteasome as a protease, whereas in other conditions it recognizes the proteasome as a prey. The regulation of this intricate "decision making" process remains elusive. 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.
关键词：proteasome ; autophagy ; ubiquitin ; degradation