Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.
Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.
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DOI：
10.1371/journal.pone.0001487
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发表时间：
2008-01-23
期刊：
影响因子：
3.7
通讯作者：
Joazeiro CA
中科院分区：
文献类型：
--
作者：
Li W;Bengtson MH;Ulbrich A;Matsuda A;Reddy VA;Orth A;Chanda SK;Batalov S;Joazeiro CA
蛋白质泛素化的特异性由E3泛素（Ub）连接酶赋予。我们已经注释了人类基因组中编码的E3复合物的1617个推定的E3和底物识别亚基。对E3超家族成员功能的了解有限，促使我们构建了用于功能筛选的全基因组E3 cDNA和RNAi表达文库。使用这些文库进行的基于成像的筛选以鉴定调节线粒体动力学的E3，发现了MULAN/FLJ 12875，这是一种RING指蛋白，其异位表达和敲低均干扰线粒体运输和形态。我们发现MULAN是一种线粒体蛋白-两个跨膜结构域介导其定位到细胞器的外膜。MULAN被定向为使得其E3活性的C末端RING指暴露于胞质溶胶，在胞质溶胶中它可以接触到Ub系统的其他组分。完整的环指和正确的亚细胞定位都是调节线粒体动力学所必需的，这表明MULAN的下游效应子是与线粒体整合或相关的蛋白质，并且被Ub修饰。有趣的是，MULAN先前已被鉴定为NF-κB的激活剂，从而提供了线粒体动力学和细胞核信号传导之间的联系。这些发现表明存在一种新的，Ub介导的机制，负责将线粒体整合到细胞环境中。
Specificity of protein ubiquitylation is conferred by E3 ubiquitin (Ub) ligases. We have annotated ∼617 putative E3s and substrate-recognition subunits of E3 complexes encoded in the human genome. The limited knowledge of the function of members of the large E3 superfamily prompted us to generate genome-wide E3 cDNA and RNAi expression libraries designed for functional screening. An imaging-based screen using these libraries to identify E3s that regulate mitochondrial dynamics uncovered MULAN/FLJ12875, a RING finger protein whose ectopic expression and knockdown both interfered with mitochondrial trafficking and morphology. We found that MULAN is a mitochondrial protein – two transmembrane domains mediate its localization to the organelle's outer membrane. MULAN is oriented such that its E3-active, C-terminal RING finger is exposed to the cytosol, where it has access to other components of the Ub system. Both an intact RING finger and the correct subcellular localization were required for regulation of mitochondrial dynamics, suggesting that MULAN's downstream effectors are proteins that are either integral to, or associated with, mitochondria and that become modified with Ub. Interestingly, MULAN had previously been identified as an activator of NF-κB, thus providing a link between mitochondrial dynamics and mitochondria-to-nucleus signaling. These findings suggest the existence of a new, Ub-mediated mechanism responsible for integration of mitochondria into the cellular environment.
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影响因子：
4.8
作者：
Neutzner, A;Youle, RJ
通讯作者：
Youle, RJ
环手指（RBR）蛋白质家族之间的环。
影响因子：
12.3
作者：
Eisenhaber B;Chumak N;Eisenhaber F;Hauser MT
通讯作者：
Hauser MT
在酿酒酵母中，泛素化在线粒体遗传中的作用。
影响因子：
7.8
作者：
Fisk, H A;Yaffe, M P
通讯作者：
Yaffe, M P
影响因子：
64.8
作者：
Karbowski, Mariusz;Norris, Kristi L.;Youle, Richard J.
通讯作者：
Youle, Richard J.
影响因子：
3.3
作者：
Fritz, S;Weinbach, N;Westermann, B
通讯作者：
Westermann, B