Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system.
Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system.
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Xu D;Shan B;Lee BH;Zhu K;Zhang T;Sun H;Liu M;Shi L;Liang W;Qian L;Xiao J;Wang L;Pan L;Finley D;Yuan J
泛蛋白-蛋白酶体系统（UPS）控制真核细胞中短寿命蛋白质的周转，其调节对于维持细胞蛋白质稳态至关重要。在这里，我们表明，USP 14，一个主要的去泛素化酶，调节UPS，是一个底物的Akt，丝氨酸/苏氨酸特异性蛋白激酶的关键介导细胞内信号转导生长因子。我们报告说，Akt介导的磷酸化USP 14在Ser 432，这通常会阻止其催化位点的非活性构象，激活其去泛素化活性在体外和细胞中。我们还证明了USP 14的磷酸化对于Akt调节蛋白酶体活性和因此的全球蛋白质降解是至关重要的。由于Akt可以被广泛的生长因子激活，并在磷酸肌醇磷酸酶PTEN的负控制下，我们认为，由Akt介导的USP 14磷酸化调节UPS可能为生长因子提供了一种共同的机制，以控制全球蛋白质稳态和促进PTEN阴性癌细胞的肿瘤发生。DOI：http://dx.doi.org/10.7554/eLife.10510.001蛋白质是细胞的主要组成部分。这些分子提供结构，传递信息并执行许多其他基本任务。当蛋白质完成了它们的目的，或者被损坏时，它们必须通过细胞中称为蛋白酶体的垃圾处理器样分子机器被去除。蛋白酶体的分解可能导致人类疾病，如癌症和神经变性。细胞有一个系统可以识别和标记蛋白质以进行破坏，另一个系统可以抵消这一过程并使蛋白质免于破坏。这两个系统的精确调节有助于确保细胞的健康平衡。一种可以从蛋白酶体中释放蛋白质的酶被称为USP 14。以前，这种酶被称为当它与蛋白质处理机器连接时被打开，以控制哪些蛋白质被破坏。但是，细胞中的许多USP 14酶与这种蛋白酶体机制无关，目前还不清楚这些“游离”酶是否以及如何对细胞重要。现在，Xu等人报道了一种可以开启USP 14的新机制：另一种称为Akt的酶可以通过在USP 14的特定位点添加磷酸基团来开启USP 14。Akt是一种重要的信号分子，在许多肿瘤细胞中被激活以促进细胞的生长和增殖。Xu等人发现，通过控制USP 14的活性，Akt可以控制蛋白质处理机制的活性，进而调节许多其他蛋白质的水平。这些发现表明，在Akt活性升高的肿瘤细胞中USP 14的异常活性可能有助于癌症形成。DOI：http://dx.doi.org/10.7554/eLife.10510.002网站
Regulation of ubiquitin-proteasome system (UPS), which controls the turnover of short-lived proteins in eukaryotic cells, is critical in maintaining cellular proteostasis. Here we show that USP14, a major deubiquitinating enzyme that regulates the UPS, is a substrate of Akt, a serine/threonine-specific protein kinase critical in mediating intracellular signaling transducer for growth factors. We report that Akt-mediated phosphorylation of USP14 at Ser432, which normally blocks its catalytic site in the inactive conformation, activates its deubiquitinating activity in vitro and in cells. We also demonstrate that phosphorylation of USP14 is critical for Akt to regulate proteasome activity and consequently global protein degradation. Since Akt can be activated by a wide range of growth factors and is under negative control by phosphoinosotide phosphatase PTEN, we suggest that regulation of UPS by Akt-mediated phosphorylation of USP14 may provide a common mechanism for growth factors to control global proteostasis and for promoting tumorigenesis in PTEN-negative cancer cells. DOI: http://dx.doi.org/10.7554/eLife.10510.001 Proteins are the workhorses of cells. These molecules provide structure, transmit messages and carry out many other essential tasks. When proteins have fulfilled their purpose, or become damaged, they must be removed through a garbage disposal-like molecular machine in cells called the proteasome. A breakdown in the proteasome may lead to diseases in humans such as cancers and neurodegeneration. Cells have a system that can identify and mark proteins for destruction, and another system that counteracts this process and spares proteins from destruction. Precise regulation of these two systems helps ensure a healthy balance in cells. One enzyme that can spare proteins from the proteasome is called USP14. Previously, this enzyme is known to be switched on when it connects with the protein disposal machinery to control which proteins get destroyed. But, many of the USP14 enzymes in cells are not associated with this proteasome machinery and it was unclear if and how these ‘free’ enzymes might be important for the cell. Now, Xu et al. report a new mechanism that can switch on USP14: another enzyme called Akt can switch on USP14 by adding a phosphate group to a specific site in USP14. Akt is an important signaling molecule that is activated in many tumor cells to promote the growth and multiplication of cells. Xu et al. discovered that by controlling USP14 activity, Akt can control the activity of the protein disposal machinery that in turn regulates the levels of many other proteins. These findings suggest that abnormal activity of USP14 in tumor cells with elevated Akt activity may contribute to cancer formation. DOI: http://dx.doi.org/10.7554/eLife.10510.002