USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons.
USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons.
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应激诱导的线粒体自噬是一种受到严格调控的过程，其目标是功能失调的线粒体进行自噬依赖性降解，主要依赖于两种蛋白，PINK1和Parkin，这两种基因在某些常见的帕金森病（PD）中发生突变。当线粒体损伤时，蛋白激酶PINK1积聚在细胞器表面，控制e3 -泛素连接酶Parkin的募集。在线粒体上，Parkin泛素化位于线粒体外膜上的线粒体驻留蛋白亚群，导致下游细胞质自噬接头的募集和随后的自噬体形成。重要的是，PINK1/帕金森无关的有丝自噬途径也存在，可以被特异性去泛素化酶（DUBs）抵消。这些特异性dub的下调可能会增强基础线粒体自噬，并且在涉及缺陷线粒体积累的模型中是有益的。在这些dub中，USP8是一个有趣的靶点，因为它在内体途径和自噬中发挥作用，并且在神经变性模型中被抑制时具有有益作用。在此基础上，我们评估了USP8活性改变时的自噬和有丝自噬水平。我们使用遗传方法在体内测量黑腹巨噬菌的自噬和线粒体自噬，并在体外研究通过USP8调节线粒体自噬的分子途径。我们发现基础线粒体自噬与USP8水平呈负相关，USP8的下调与帕金森非依赖性线粒体自噬的增加相关。这些结果表明存在一种尚未表征的被USP8抑制的有丝分裂途径。
Stress-induced mitophagy, a tightly regulated process that targets dysfunctional mitochondria for autophagy-dependent degradation, mainly relies on two proteins, PINK1 and Parkin, which genes are mutated in some forms of familiar Parkinson’s Disease (PD). Upon mitochondrial damage, the protein kinase PINK1 accumulates on the organelle surface where it controls the recruitment of the E3-ubiquitin ligase Parkin. On mitochondria, Parkin ubiquitinates a subset of mitochondrial-resident proteins located on the outer mitochondrial membrane, leading to the recruitment of downstream cytosolic autophagic adaptors and subsequent autophagosome formation. Importantly, PINK1/Parkin-independent mitophagy pathways also exist that can be counteracted by specific deubiquitinating enzymes (DUBs). Down-regulation of these specific DUBs can presumably enhance basal mitophagy and be beneficial in models in which the accumulation of defective mitochondria is implicated. Among these DUBs, USP8 is an interesting target because of its role in the endosomal pathway and autophagy and its beneficial effects, when inhibited, in models of neurodegeneration. Based on this, we evaluated autophagy and mitophagy levels when USP8 activity is altered. We used genetic approaches in D. melanogaster to measure autophagy and mitophagy in vivo and complementary in vitro approaches to investigate the molecular pathway that regulates mitophagy via USP8. We found an inverse correlation between basal mitophagy and USP8 levels, in that down-regulation of USP8 correlates with increased Parkin-independent mitophagy. These results suggest the existence of a yet uncharacterized mitophagic pathway that is inhibited by USP8.
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