Unfolding is the driving force for mitochondrial import and degradation of the Parkinson's disease-related protein DJ-1.
Unfolding is the driving force for mitochondrial import and degradation of the Parkinson's disease-related protein DJ-1.
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DOI：
10.1242/jcs.258653
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发表时间：
2021-11-15
影响因子：
4
通讯作者：
Matsuda N
中科院分区：
文献类型：
--
作者：
Queliconi BB;Kojima W;Kimura M;Imai K;Udagawa C;Motono C;Hirokawa T;Tashiro S;Caaveiro JMM;Tsumoto K;Yamano K;Tanaka K;Matsuda N
与家族性帕金森病（家族性帕金森综合征）相关的不同基因涉及线粒体质量控制。其中一个基因PARK 7编码蛋白DJ-1，其致病性突变触发其从细胞质易位到线粒体基质。稳态胞质蛋白如DJ-1在错义突变后易位到线粒体基质是罕见的，其潜在机制仍有待阐明。在这里，我们表明，与各种DJ-1突变相关的蛋白质展开驱动其导入线粒体基质。增加这些DJ-1突变体的结构稳定性恢复胞质定位。从机制上讲，我们发现DJ-1结构稳定性的降低暴露了一个隐藏的N-末端线粒体靶向信号（MTS），包括Leu 10，它促进DJ-1进入线粒体基质进行随后的降解。我们的工作描述了一种新的细胞机制，将不稳定的胞质蛋白质靶向线粒体进行降解。帕金森病相关蛋白DJ-1的几个突变导致其线粒体输入和降解。我们揭示了蛋白质解折叠是DJ-1的输入和降解的驱动力。
Diverse genes associated with familial Parkinson's disease (familial Parkinsonism) have been implicated in mitochondrial quality control. One such gene, PARK7 encodes the protein DJ-1, pathogenic mutations of which trigger its translocation from the cytosol to the mitochondrial matrix. The translocation of steady-state cytosolic proteins like DJ-1 to the mitochondrial matrix upon missense mutations is rare, and the underlying mechanism remains to be elucidated. Here, we show that the protein unfolding associated with various DJ-1 mutations drives its import into the mitochondrial matrix. Increasing the structural stability of these DJ-1 mutants restores cytosolic localization. Mechanistically, we show that a reduction in the structural stability of DJ-1 exposes a cryptic N-terminal mitochondrial-targeting signal (MTS), including Leu10, which promotes DJ-1 import into the mitochondrial matrix for subsequent degradation. Our work describes a novel cellular mechanism for targeting a destabilized cytosolic protein to the mitochondria for degradation. Summary: Several mutations in Parkinson's disease-related protein DJ-1 cause its mitochondrial import and degradation. We reveal that protein unfolding is the driving force for the import and degradation of DJ-1.
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Heutink, P