Regulation of Met1-linked polyubiquitin signalling by the deubiquitinase OTULIN.
Regulation of Met1-linked polyubiquitin signalling by the deubiquitinase OTULIN.
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DOI：
10.1111/febs.13547
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Komander D
中科院分区：
文献类型：
--
作者：
Elliott PR;Komander D
Met 1连接的“线性”泛素链修饰蛋白质已成为通过主调节因子--转录因子核因子κB（NF-κB）控制炎症信号传导的关键调节信号。虽然组装机器，线性泛素链组装复合物（LUBAC），和这种泛素链类型的受体已经知道了多年，它是不太清楚的去泛素化酶（DUBs）水解Met 1键特异性。2013年，两个实验室报告了以前未注释的蛋白质FAM 105 B/OTULIN是这种缺失的Met 1连锁特异性DUB。结构研究揭示了OTULIN如何利用泛蛋白辅助催化机制实现其显着的特异性，其中底物上的谷氨酸残基补充了酶的活性位点。OTULIN的特异性使其能够调节细胞中Met 1连接的多聚泛素的整体水平。这种能力导致从新的角度研究NF-κB活化，也揭示了Met 1-聚泛素参与Wnt信号传导。有趣的是，OTULIN直接与LUBAC相互作用，这种相互作用是动态的，可以通过OTULIN磷酸化来调节。这为如何通过介导组装和去除的专用酶复合物来调节单个连接类型提供了新的范式。在这里，我们回顾了关于OTULIN的机制，调节和功能的知识，讨论了该领域的开放性问题，并讨论了DUBs如何调节NF-κB反应。
Modification of proteins with Met1‐linked ‘linear’ ubiquitin chains has emerged as a key regulatory signal to control inflammatory signalling via the master regulator, the transcription factor nuclear factor κB (NF‐κB). While the assembly machinery, the linear ubiquitin chain assembly complex (LUBAC), and receptors for this ubiquitin chain type have been known for years, it was less clear which deubiquitinating enzymes (DUBs) hydrolyse Met1 linkages specifically. In 2013, two labs reported the previously unannotated protein FAM105B/OTULIN to be this missing Met1 linkage‐specific DUB. Structural studies have revealed how OTULIN achieves its remarkable specificity, employing a mechanism of ubiquitin‐assisted catalysis in which a glutamate residue on the substrate complements the active site of the enzyme. The specificity of OTULIN enables it to regulate global levels of Met1‐linked polyubiquitin in cells. This ability led to investigations of NF‐κB activation from new angles, and also revealed involvement of Met1‐polyubiquitin in Wnt signalling. Interestingly, OTULIN directly interacts with LUBAC, and this interaction is dynamic and can be regulated by OTULIN phosphorylation. This provides a new paradigm for how individual linkage types can be regulated by dedicated enzyme complexes mediating assembly and removal. Here we review what has been learned about OTULIN's mechanism, regulation and function, discuss the open questions in the field, and discuss how DUBs regulate the NF‐κB response.