UBXD1 is a mitochondrial recruitment factor for p97/VCP and promotes mitophagy
UBXD1 is a mitochondrial recruitment factor for p97/VCP and promotes mitophagy
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DOI：
10.1038/s41598-018-30963-z
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发表时间：
2018-08-17
影响因子：
4.6
通讯作者：
Neutzner, Albert
中科院分区：
文献类型：
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作者：
Bento, Ana C.;Bippes, Claudia C.;Neutzner, Albert
通过线粒体自噬清除受损的线粒体对于维持线粒体保真度和预防神经变性至关重要。在这里，我们报告的UBX结构域，p97/VCP辅因子UBXD 1/UBXN 6/UBXDC 2及其在线粒体自噬的作用。通过其C-末端UBX结构域识别去极化线粒体，UBXD 1以帕金森依赖性方式易位至线粒体。在帕金森非依赖性线粒体自噬过程中，UBXD 1没有显示线粒体易位。一旦易位，UBXD 1通过由其N-末端Vim和PUB结构域组成的二分结合基序将p97募集到线粒体。UBXD 1对p97的募集仅依赖于UBXD 1在线粒体上的存在，而不需要进一步的线粒体信号。在UBXD 1易位到CCCP去极化线粒体和p97募集后，LC 3阳性自溶酶体的形成强烈增强，线粒体的自噬降解显著加速。CCCP处理后，UBXD 1水平降低对表达Parkin的细胞中的线粒体吞噬通量产生负面影响。因此，我们的数据支持一种模型，即p97辅因子UBXD 1通过特异性识别受损的线粒体进行自噬清除来促进帕金森依赖性线粒体自噬。
Clearance of damaged mitochondria through mitophagy is critical for maintaining mitochondrial fidelity and the prevention of neurodegeneration. Here, we report on the UBX domain-containing, p97/VCP cofactor UBXD1/UBXN6/UBXDC2 and its role in mitophagy. Recognizing depolarized mitochondria via its C-terminal UBX domain, UBXD1 translocates to mitochondria in a Parkin-dependent manner. During Parkin-independent mitophagy, UBXD1 shows no mitochondrial translocation. Once translocated, UBXD1 recruits p97 to mitochondria via a bipartite binding motif consisting of its N-terminal VIM and PUB domains. Recruitment of p97 by UBXD1 only depends on the presence of UBXD1 on mitochondria without the need for further mitochondrial signals. Following translocation of UBXD1 to CCCP-depolarized mitochondria and p97 recruitment, formation of LC3-positive autolysosomes is strongly enhanced and autophagic degradation of mitochondria is significantly accelerated. Diminished levels of UBXD1 negatively impact mitophagic flux in Parkin-expressing cells after CCCP treatment. Thus, our data supports a model, whereby the p97 cofactor UBXD1 promotes Parkin-dependent mitophagy by specifically recognizing damaged mitochondria undergoing autophagic clearance.