Suppression of ATG4B by copper inhibits autophagy and involves in Mallory body formation.
Suppression of ATG4B by copper inhibits autophagy and involves in Mallory body formation.
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DOI：
10.1016/j.redox.2022.102284
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发表时间：
2022-06
期刊：
影响因子：
11.4
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Xia F;Fu Y;Xie H;Chen Y;Fang D;Zhang W;Liu P;Li M
自噬是一种进化上保守的自我保护机制，与细胞内稳态有关。ATG4B通过承担LC 3的引发和脱脂在自噬过程中起着至关重要的作用。已经证明化学抑制剂和调节修饰（例如ATG4B的氧化）调节自噬功能。ATG4B是否以及如何受到金属离子的调节在很大程度上是未知的。铜是人体生理过程中氧化还原反应中的一种重要的微量元素。铜在ATP 7 B突变细胞中的过量蓄积导致病理进展，例如Wilson病（WD）中的不溶性马洛里体（MB）。通过自噬途径清除MB被认为是治疗WD的一个有前途的策略。在此，我们发现铜离子而不是其他离子可以抑制ATG4B的活性，随后抑制自噬。此外，铜可以诱导依赖于半胱氨酸氧化的ATG4B寡聚体，这可以在还原条件下消除。铜还促进不溶性ATG4B聚集体以及p62和泛素阳性聚集体的形成，这与WD细胞模型中铜过载引起的MB组分一致。重要的是，ATG4B的过表达可以部分减少MB的形成并挽救受损的自噬。总之，我们的研究结果首次揭示了铜介导的新的损伤机制，并暗示了铜毒性和自噬在WD发病机制中的相互作用的新见解。铜在体外和细胞中抑制ATG4B的活性。铜通过抑制ATG4B阻断自噬。铜诱导的ATG4B聚集和寡聚化依赖于半胱氨酸氧化。过表达ATG4 B可减少铜负荷肝豆状核变性模型中马洛里小体的形成。
Autophagy is an evolutionarily conserved self-protecting mechanism implicated in cellular homeostasis. ATG4B plays a vital role in autophagy process via undertaking priming and delipidation of LC3. Chemical inhibitors and regulative modifications such as oxidation of ATG4B have been demonstrated to modulate autophagy function. Whether and how ATG4B could be regulated by metal ions is largely unknown. Copper is an essential trace metal served as static co-factors in redox reactions in physiology process. Excessive accumulation of copper in ATP7B mutant cells leads to pathology progression such as insoluble Mallory body (MB) in Wilson disease (WD). The clearance of MB via autophagy pathway was thought as a promising strategy for WD. Here, we discovered that copper ion instead of other ions could inhibit the activity of ATG4B followed by autophagy suppression. In addition, copper could induce ATG4B oligomers depending on cysteine oxidation which could be abolished in reduced condition. Copper also promotes the formation of insoluble ATG4B aggregates, as well as p62-and ubiquitin-positive aggregates, which is consistent with the components of MB caused by copper overload in WD cell model. Importantly, overexpression of ATG4B could partially reduce the formation of MB and rescue impaired autophagy. Taken together, our results uncovered for the first time a new damage mechanism mediated by copper and implied new insights of the crosstalk between the toxicity of copper and autophagy in the pathogenesis of WD. Copper inhibits the activity of ATG4B in vitro and in cells. Copper blocks autophagy via the inhibition of ATG4B. Copper-induced ATG4B aggregation and oligomerization depend on cysteine oxidation. Overexpression of ATG4B could reduce the formation of Mallory body in copper overload Wilson disease model.
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影响因子：
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作者：
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通讯作者：
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影响因子：
82.9
作者：
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影响因子：
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作者：
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影响因子：
13.3
作者：
Li, Yazi;Zhang, Yuying;Chen, Chang
通讯作者：
Chen, Chang
DOI：
10.1016/j.bbrc.2018.06.153
发表时间：
2018-09-18
影响因子：
3.1
作者：
Cabe M;Rademacher DJ;Karlsson AB;Cherukuri S;Bakowska JC
通讯作者：
Bakowska JC