The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy
The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy
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DOI：
10.1038/cdd.2009.200
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发表时间：
2010-06-01
影响因子：
12.4
通讯作者：
Casari, G.
中科院分区：
文献类型：
--
作者：
Michiorri, S.;Gelmetti, V.;Casari, G.
PINK1基因突变导致常染色体隐性帕金森病。PINK1基因编码一种蛋白激酶，该蛋白激酶通过线粒体裂解产生两个成熟的同工型。除了对线粒体功能障碍和凋亡的保护作用外，PINK1还调节pd相关蛋白Parkin上游的线粒体动力学。最近的数据显示，线粒体Parkin促进功能失调线粒体的自噬降解，稳定的PINK1沉默可能在线粒体自噬激活中起间接作用。在这里，我们报道了PINK1和Beclin1之间的新相互作用，Beclin1是一种关键的促自噬蛋白，已经涉及阿尔茨海默病和亨廷顿病的发病机制。相互作用需要PINK1的N端和c端，这表明全长PINK1与Beclin1相互作用，而不是其裂解异构体。我们还证明，PINK1显著增强了基础和饥饿诱导的自噬，这可以通过降低Beclin1表达或抑制Beclin1伴侣Vps34来减少。突变体PINK1（W437X）与Beclin1的相互作用很大程度上受损，缺乏增强自噬的能力，而PINK1（G309D）则没有观察到这种情况，PINK1（G309D）是一个激酶活性缺陷但与Beclin1结合能力不变的突变体。这些发现确定了PINK1的新功能，并进一步加强了自噬和涉及神经退行性过程的蛋白质之间的联系。细胞死亡与分化（2010）17,962-974；doi: 10.1038 / cdd.2009.200;2010年1月8日在线发布
Mutations in the PINK1 gene cause autosomal recessive Parkinson's disease. The PINK1 gene encodes a protein kinase that is mitochondrially cleaved to generate two mature isoforms. In addition to its protective role against mitochondrial dysfunction and apoptosis, PINK1 is also known to regulate mitochondrial dynamics acting upstream of the PD-related protein Parkin. Recent data showed that mitochondrial Parkin promotes the autophagic degradation of dysfunctional mitochondria, and that stable PINK1 silencing may have an indirect role in mitophagy activation. Here we report a new interaction between PINK1 and Beclin1, a key pro-autophagic protein already implicated in the pathogenesis of Alzheimer's and Huntington's diseases. Both PINK1 N- and C-terminal are required for the interaction, suggesting that full-length PINK1, and not its cleaved isoforms, interacts with Beclin1. We also demonstrate that PINK1 significantly enhances basal and starvation-induced autophagy, which is reduced by knocking down Beclin1 expression or by inhibiting the Beclin1 partner Vps34. A mutant, PINK1(W437X), interaction of which with Beclin1 is largely impaired, lacks the ability to enhance autophagy, whereas this is not observed for PINK1(G309D), a mutant with defective kinase activity but unaltered ability to bind Beclin1. These findings identify a new function of PINK1 and further strengthen the link between autophagy and proteins implicated in the neurodegenerative process. Cell Death and Differentiation (2010) 17, 962-974; doi:10.1038/cdd.2009.200; published online 8 January 2010