VCP cooperates with UBXD1 to degrade mitochondrial outer membrane protein MCL1 in model of Huntington's disease.
VCP cooperates with UBXD1 to degrade mitochondrial outer membrane protein MCL1 in model of Huntington's disease.
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DOI：
10.1016/j.bbadis.2016.11.026
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发表时间：
2017-02
影响因子：
6.2
通讯作者：
Qi, Xin
中科院分区：
文献类型：
--
作者：
Guo, Xing;Qi, Xin
线粒体外膜（OMM）相关蛋白的蛋白酶体依赖性周转是维持线粒体正常质量和功能的机制之一。然而，对人类疾病的潜在途径及其影响知之甚少。亨廷顿病（HD）是一种致命的遗传性神经退行性疾病，由亨廷顿蛋白基因（突变亨廷顿蛋白，mtHtt）N末端的CAG重复序列扩增引起。在这项研究中，我们显示了在HD小鼠纹状体细胞和HD患者成纤维细胞中OMM蛋白MCL 1（髓样细胞白血病序列1）的广泛降解。MCL 1水平的降低与线粒体和细胞损伤有关。Valosin-containing-protein（VCP）是一种AAA-ATP酶，通过泛素蛋白酶体系统（UPS）参与蛋白质的转换。我们发现，VCP易位到线粒体和促进MCL 1降解HD细胞培养。通过RNA干扰下调VCP或通过显性负突变体抑制VCP可消除HD细胞培养物中的MCL 1降解。我们进一步表明，含有UBX结构域的蛋白1（UBXD 1）是VCP的已知辅助因子，有助于识别蛋白质降解的底物，它选择性地与MCL 1结合并与VCP相互作用，以介导MCL 1从线粒体中提取。这些结果表明，OMM蛋白MCL 1被VCP-UBXD 1复合物降解，并且该过程被mtHtt的存在促进。因此，我们的发现为HD中线粒体功能障碍的机制提供了新的见解。
Proteasome-dependent turnover of mitochondrial outer membrane (OMM)-associated proteins is one of the mechanisms for maintaining proper mitochondrial quality and function. However, the underlying pathways and their implications in human disease are poorly understood. Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder caused by expanded CAG repeats in the N terminal of the huntingtin gene (mutant Huntingtin, mtHtt). In this study, we show an extensive degradation of the OMM protein MCL1 (Myeloid cell leukemia sequence 1) in both HD mouse striatal cells and HD patient fibroblasts. The decrease in MCL1 level is associated with mitochondrial and cellular damage. Valosin-containing-protein (VCP) is an AAA-ATPase central to protein turnover via the ubiquitin proteasome system (UPS). We found that VCP translocates to mitochondria and promotes MCL1 degradation in HD cell cultures. Either down-regulation of VCP by RNA interference or inhibition of VCP by a dominant negative mutant abolishes MCL1 degradation in HD cell cultures. We further show that UBX-domain containing protein 1 (UBXD1), a known co-factor of VCP assisting in the recognition of substrates for protein degradation, selectively binds to MCL1 and interacts with VCP to mediate MCL1 extraction from the mitochondria. These results indicate that the OMM protein MCL1 is degraded by the VCP-UBXD1 complex and that the process is promoted by the presence of mtHtt. Therefore, our finding provides a new insight into the mechanism of mitochondrial dysfunction in HD.
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影响因子：
16
作者：
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