HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis.
HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis.
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DOI：
10.1080/15548627.2016.1248018
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发表时间：
2017-01-02
期刊：
影响因子：
13.3
通讯作者：
Tanaka M
中科院分区：
文献类型：
--
作者：
Watanabe Y;Tsujimura A;Taguchi K;Tanaka M
Proteostasis是保护细胞免受有害蛋白侵害的重要机制，主要受HSF1（热休克转录因子1）应激反应通路控制。该途径通过分子伴侣促进蛋白质的再折叠；然而，尚不清楚它是否参与自噬或包涵体的形成。自噬受体SQSTM1/p62参与有害蛋白的选择性自噬清除和包涵形成，其在S349、S403和S407位点的磷酸化是与底物结合所必需的。在这里，我们证明了当有害蛋白积累时，酪蛋白激酶1磷酸化SQSTM1 S349残基。上游因子的研究表明，SQSTM1 S349和SQSTM1 S403残基都以HSF1依赖的方式磷酸化。抑制SQSTM1磷酸化抑制泛素化蛋白的包涵体形成，并阻止SQSTM1与聚集倾向蛋白的共定位。此外，HSF1抑制损害了聚集体诱导的自噬体的形成和蛋白质聚集体的消除。我们的研究结果表明HSF1可触发sqstm1介导的蛋白停滞。
Proteostasis is important for protecting cells from harmful proteins and is mainly controlled by the HSF1 (heat shock transcription factor 1) stress response pathway. This pathway facilitates protein refolding by molecular chaperones; however, it is unclear whether it functions in autophagy or inclusion formation. The autophagy receptor SQSTM1/p62 is involved in selective autophagic clearance and inclusion formation by harmful proteins, and its phosphorylation at S349, S403, and S407 is required for binding to substrates. Here, we demonstrate that casein kinase 1 phosphorylates the SQSTM1 S349 residue when harmful proteins accumulate. Investigation of upstream factors showed that both SQSTM1 S349 and SQSTM1 S403 residues were phosphorylated in an HSF1 dependent manner. Inhibition of SQSTM1 phosphorylation suppressed inclusion formation by ubiquitinated proteins and prevented colocalization of SQSTM1 with aggregation-prone proteins. Moreover, HSF1 inhibition impaired aggregate-induced autophagosome formation and elimination of protein aggregates. Our findings indicate that HSF1 triggers SQSTM1-mediated proteostasis.