JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis.
JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis.
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DOI：
10.1083/jcb.201303066
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发表时间：
2013-09-02
期刊：
影响因子：
--
通讯作者：
Lewcock JW
中科院分区：
文献类型：
--
作者：
Huntwork-Rodriguez S;Wang B;Watkins T;Ghosh AS;Pozniak CD;Bustos D;Newton K;Kirkpatrick DS;Lewcock JW
神经元损伤诱导DLK的JNK磷酸化，其减少DLK泛素化并产生正反馈环以增强JNK信号传导并增加凋亡。神经元是高度极化的细胞，其通常将轴突投射相当远的距离。为了对轴突损伤做出反应，神经元必须向细胞核传递逆行信号以实现转录应激反应。在这里，我们描述了一种机制，该信号通过损伤诱导的双亮氨酸拉链轴承激酶（DLK/MAP 3 K12）的稳定传播。神经元损伤后，DLK全长的特定位点经历c-Jun N末端激酶（JNK）的磷酸化，这些激酶已被证明是DLK途径活性的下游靶点。这些磷酸化事件通过减少DLK泛素化导致DLK丰度增加，这是由E3泛素连接酶PHR 1和去泛素化酶USP 9 X介导的。DLK的缺失反过来控制下游JNK信号转导和细胞凋亡的水平。通过这种反馈机制，泛素-蛋白酶体系统能够提供逆行应激信号传导的额外调节层，以产生对局部外部损伤的整体细胞反应。
Neuronal injury induces JNK phosphorylation of DLK, which reduces DLK ubiquitination and creates a positive feedback loop to enhance JNK signaling and increase apoptosis. Neurons are highly polarized cells that often project axons a considerable distance. To respond to axonal damage, neurons must transmit a retrograde signal to the nucleus to enable a transcriptional stress response. Here we describe a mechanism by which this signal is propagated through injury-induced stabilization of dual leucine zipper-bearing kinase (DLK/MAP3K12). After neuronal insult, specific sites throughout the length of DLK underwent phosphorylation by c-Jun N-terminal kinases (JNKs), which have been shown to be downstream targets of DLK pathway activity. These phosphorylation events resulted in increased DLK abundance via reduction of DLK ubiquitination, which was mediated by the E3 ubiquitin ligase PHR1 and the de-ubiquitinating enzyme USP9X. Abundance of DLK in turn controlled the levels of downstream JNK signaling and apoptosis. Through this feedback mechanism, the ubiquitin–proteasome system is able to provide an additional layer of regulation of retrograde stress signaling to generate a global cellular response to localized external insults.
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影响因子：
6.1
作者：
Fernandes, Kimberly A.;Harder, Jeffrey M.;Fornarola, Laura B.;Freeman, Robert S.;Clark, Abbot F.;Pang, Iok-Hou;John, Simon W. M.;Libby, Richard T.
通讯作者：
Libby, Richard T.
影响因子：
4.4
作者：
Bakalarski, Corey E.;Elias, Joshua E.;Villen, Judit;Haas, Wilhelm;Gerber, Scott A.;Everley, Patrick A.;Gygi, Steven P.
通讯作者：
Gygi, Steven P.
影响因子：
7.8
作者：
Cavalli, V;Kujala, P;Goldstein, LSB
通讯作者：
Goldstein, LSB
影响因子：
4.8
作者：
Leung, IWL;Lassam, N
通讯作者：
Lassam, N
影响因子：
64.8
作者：
Erkman, L;McEvilly, RJ;Rosenfeld, MG
通讯作者：
Rosenfeld, MG