The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.
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DOI：
10.1371/journal.pbio.1001440
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Collins CA
中科院分区：
文献类型：
--
作者：
Xiong X;Hao Y;Sun K;Li J;Li X;Mishra B;Soppina P;Wu C;Hume RI;Collins CA
Highwire是一种保守的轴突E3泛素连接酶，通过调节NAD+生物合成酶Nmnat和Wnd激酶的水平来调节果蝇损伤后轴突变性的起始。轴突变性是许多神经病变、神经变性疾病和损伤的标志。在这里，使用果蝇损伤模型，我们已经确定了一个高度保守的E3泛素连接酶，高线（Hiw），作为一个重要的调节轴突和突触变性。hiw突变强烈抑制多种神经元类型和发育阶段的沃勒变性。这种新的表型是由Hiw的一个新的下游靶点介导的：NAD+生物合成酶烟酰胺单核苷酸腺苷转移酶（Nmnat），它与Hiw以前已知的靶点瓦伦达双亮氨酸拉链激酶（Wnd/DLK）MAPKKK平行作用。Hiw促进损伤后远端残端Nmnat蛋白的快速消失。hiw突变体中Nmnat蛋白水平的增加是抑制变性所需的并且是足够的。异位表达的小鼠Nmnat 2也受到Hiw在远端轴突和突触中的调节。这些发现暗示了内源性Nmnat及其调节的重要作用，通过保守的机制，在轴突变性的启动。通过Wnd/DLK的独立调节，其功能是近端轴突再生所必需的，Hiw在协调轴突损伤的再生和退行性反应中起着核心作用。轴突在损伤后和神经退行性疾病期间退化，但我们仍在寻找导致这种退化的细胞机制。在这里，使用神经挤压损伤试验在果蝇，我们已经确定了一个保守的分子命名为Highwire（HiW）在轴突变性的启动中的作用。Hiw是一种E3泛素连接酶，被认为通过靶向破坏特定下游蛋白质来调节其水平。我们表明，Hiw通过调节两个独立的下游靶点促进轴突变性：Wallenda（Wnd）激酶和NAD+生物合成酶烟酰胺单核苷酸腺苷转移酶（Nmnat）。有趣的是，Nmnat以前被认为在神经元中具有保护作用。我们的研究结果表明，Nmnat蛋白在轴突中被Hiw下调，并且这种调节在轴突和突触的变性中起关键作用。另一个靶点是Wnd激酶，以前已知其在损伤后促进新轴突生长中的作用。我们提出，Hiw协调多种反应，以再生损伤后的神经元回路：通过Nmnat的远端轴突的变性，和通过Wnd的近端轴突的新生长。
Highwire, a conserved axonal E3 ubiquitin ligase, regulates the initiation of axonal degeneration after injury in Drosophila by regulating the levels of the NAD+ biosynthetic enzyme, Nmnat, and the Wnd kinase. Axonal degeneration is a hallmark of many neuropathies, neurodegenerative diseases, and injuries. Here, using a Drosophila injury model, we have identified a highly conserved E3 ubiquitin ligase, Highwire (Hiw), as an important regulator of axonal and synaptic degeneration. Mutations in hiw strongly inhibit Wallerian degeneration in multiple neuron types and developmental stages. This new phenotype is mediated by a new downstream target of Hiw: the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat), which acts in parallel to a previously known target of Hiw, the Wallenda dileucine zipper kinase (Wnd/DLK) MAPKKK. Hiw promotes a rapid disappearance of Nmnat protein in the distal stump after injury. An increased level of Nmnat protein in hiw mutants is both required and sufficient to inhibit degeneration. Ectopically expressed mouse Nmnat2 is also subject to regulation by Hiw in distal axons and synapses. These findings implicate an important role for endogenous Nmnat and its regulation, via a conserved mechanism, in the initiation of axonal degeneration. Through independent regulation of Wnd/DLK, whose function is required for proximal axons to regenerate, Hiw plays a central role in coordinating both regenerative and degenerative responses to axonal injury. Axons degenerate after injury and during neurodegenerative diseases, but we are still searching for the cellular mechanism responsible for this degeneration. Here, using a nerve crush injury assay in the fruit fly Drosophila, we have identified a role for a conserved molecule named Highwire (Hiw) in the initiation of axonal degeneration. Hiw is an E3 ubiquitin ligase thought to regulate the levels of specific downstream proteins by targeting their destruction. We show that Hiw promotes axonal degeneration by regulating two independent downstream targets: the Wallenda (Wnd) kinase, and the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat). Interestingly, Nmnat has previously been implicated in a protective role in neurons. Our findings indicate that Nmnat protein is down-regulated in axons by Hiw and that this regulation plays a critical role in the degeneration of axons and synapses. The other target, the Wnd kinase, was previously known for its role in promoting new axonal growth after injury. We propose that Hiw coordinates multiple responses to regenerate damaged neuronal circuits after injury: degeneration of the distal axon via Nmnat, and new growth of the proximal axon via Wnd.
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影响因子：
4.8
作者：
Han, Sangyeul;Witt, Rochelle M.;Ramesh, Vijaya
通讯作者：
Ramesh, Vijaya
DOI：
10.1083/jcb.200808042
发表时间：
2009-02-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Avery MA;Sheehan AE;Kerr KS;Wang J;Freeman MR
通讯作者：
Freeman MR
影响因子：
9.2
作者：
Fang, Yanshan;Soares, Lorena;Teng, Xiuyin;Geary, Melissa;Bonini, Nancy M
通讯作者：
Bonini, Nancy M
影响因子：
9.2
作者：
Avery, Michelle A;Rooney, Timothy M;Pandya, Jignesh D;Wishart, Thomas M;Gillingwater, Thomas H;Geddes, James W;Sullivan, Patrick G;Freeman, Marc R
通讯作者：
Freeman, Marc R
影响因子：
4.1
作者：
Budnik, LT;Mukhopadhyay, AK
通讯作者：
Mukhopadhyay, AK