Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism.
Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism.
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DOI：
10.1111/j.1471-4159.2009.06388.x
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发表时间：
2009-11
影响因子：
4.7
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Gal J;Ström AL;Kwinter DM;Kilty R;Zhang J;Shi P;Fu W;Wooten MW;Zhu H
在包括肌萎缩侧索硬化症(ALS)在内的神经退行性疾病中，p62/检索体1蛋白已被确定为病理蛋白包涵体的组成部分。P62还与自噬有关，自噬是细胞内蛋白质和细胞器大量降解的过程。自噬是降解错误折叠和/或受损蛋白质的关键途径，包括与家族性ALS相关的铜锌超氧化物歧化酶(SOD1)突变体。我们以前报道过p62与SOD1的ALS突变体相互作用，并且p62的泛素联合(UBA)结构域是相互作用所必需的。在本研究中，我们确定了p62的两个不同的区域，它们是p62与突变的SOD1结合所必需的：N-末端的PB1结构域(残基1-104)和一个单独的内部区域(残基178-224)，这里称为SOD1突变相互作用区(Smir)。P62的适当寡聚状态需要PB1结构域，而Smir是与突变体SOD1相互作用的实际区域。在Smir中，保守的W184、H190和带正电荷的R183、R186、K187和K189残基对p62突变的SOD1相互作用至关重要，因为这些残基被丙氨酸取代导致结合显著取消。此外，Smir和负责与Lc3相互作用的p62序列相互独立，Lc3是自噬激活所必需的蛋白质。在缺乏p62的细胞中，突变的SOD1在酸性自溶酶体中的存在减少，这表明p62可以作为突变的SOD1和自噬机制之间的适配器。本研究提供了一种新的分子机制，使突变体SOD1能够被p62以泛素不依赖的方式识别，并针对自噬-溶酶体降解途径。
The p62/sequestosome 1 protein has been identified as a component of pathological protein inclusions in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). P62 has also been implicated in autophagy, a process of mass degradation of intracellular proteins and organelles. Autophagy is a critical pathway for degrading misfolded and/or damaged proteins, including the copper-zinc superoxide dismutase (SOD1) mutants linked to familial ALS. We previously reported that p62 interacted with ALS mutants of SOD1 and that the ubiquitin-association (UBA) domain of p62 was dispensable for the interaction. In this study, we identified two distinct regions of p62 that were essential to its binding to mutant SOD1: the N-terminal PB1 domain (residues 1-104) and a separate internal region (residues 178–224) termed here as SOD1 mutant interaction region (SMIR). The PB1 domain is required for appropriate oligomeric status of p62 and the SMIR is the actual region interacting with mutant SOD1. Within the SMIR, the conserved W184, H190 and positively charged R183, R186, K187 and K189 residues are critical to the p62-mutant SOD1 interaction since substitution of these residues with alanine resulted in significantly abolished binding. In addition, SMIR and the p62 sequence responsible for the interaction with LC3, a protein essential for autophagy activation, are independent of each other. In cells lacking p62, the existence of mutant SOD1 in acidic autolysosomes decreased, suggesting that p62 can function as an adaptor between mutant SOD1 and the autophagy machinery. This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy-lysosome degradation pathway.