Unbiased proteomic screening identifies a novel role for the E3 ubiquitin ligase Nedd4-2 in translational suppression during ER stress.
Unbiased proteomic screening identifies a novel role for the E3 ubiquitin ligase Nedd4-2 in translational suppression during ER stress.
复制标题
无偏倚的蛋白质组学筛选鉴定了E3泛素连接酶Nedd4-2在内质网应激期间翻译抑制中的新作用。
DOI：
10.1111/jnc.15219
复制
发表时间：
2021-06
影响因子：
4.7
通讯作者：
Tsai NP
中科院分区：
文献类型：
--
作者：
Eagleman DE;Zhu J;Liu DC;Seimetz J;Kalsotra A;Tsai NP
当蛋白质折叠或成熟被破坏时，内质网（ER）应激发生。ER应激反应的功能障碍可导致细胞死亡，并已在许多神经系统疾病中观察到。然而，ER应激反应如何在神经元细胞中调节仍不清楚。在这里，我们研究了E3泛素连接酶命名为神经前体细胞表达发育下调蛋白4样（Nedd 4 -2）。Nedd 4 -2在大脑中高度表达，对泛素化膜结合蛋白具有高亲和力。我们首先利用无偏的蛋白质组分析与超高效液相色谱串联质谱分离的膜馏分从小鼠全脑，以确定新的目标Nedd 4 -2。通过这一筛选，我们发现核糖体蛋白的表达和泛素化受Nedd 4 -2的调控，并通过核糖体沉降和多核糖体分析证实了Nedd 4 -2与核糖体之间的关联。此外，我们利用免疫沉淀和蛋白质印迹显示，ER应激的诱导促进Nedd 4 -2和核糖体蛋白之间的关联，这是通过Nedd 4 -2在丝氨酸-342处的去磷酸化介导的。Nedd 4 -2和核糖体蛋白之间的这种增加的相互作用反过来介导ER应激相关的翻译抑制。总之，本研究的结果证明了一种新的调节机制，潜在的ER应激反应和一个新的功能，Nedd 4 -2的翻译控制。我们的研究结果可能有助于阐明ER应激反应或Nedd 4 -2功能失调的神经系统疾病。
Endoplasmic reticulum (ER) stress occurs when protein folding or maturation is disrupted. A malfunction in the ER stress response can lead to cell death and has been observed in many neurological diseases. However, how the ER stress response is regulated in neuronal cells remains largely unclear. Here, we studied an E3 ubiquitin ligase named neural precursor cell expressed developmentally downregulated protein 4-like (Nedd4-2). Nedd4-2 is highly expressed in the brain and has a high affinity toward ubiquitinating membrane-bound proteins. We first utilized unbiased proteomic profiling with ultra-performance liquid chromatography tandem mass spectrometry of isolated membrane fractions from mouse whole brains to identify novel targets of Nedd4-2. Through this screen, we found that the expression and ubiquitination of ribosomal proteins are regulated by Nedd4-2 and confirmed an association between Nedd4-2 and ribosomes through ribosome sedimentation and polysome profiling. Further, we utilized immunoprecipitation and western blotting to show that induction of ER stress promotes an association between Nedd4-2 and ribosomal proteins, which is mediated through dephosphorylation of Nedd4-2 at serine-342. This increased interaction between Nedd4-2 and ribosomal proteins in turn mediates ER stress associated translational suppression. In summary, the results of this study demonstrate a novel regulatory mechanism underlying the ER stress response and a novel function of Nedd4-2 in translational control. Our findings may shed light on neurological diseases in which the ER stress response or the function of Nedd4-2 is dysregulated.
登录
查看更多内容
影响因子：
4.8
作者：
Fotia, AB;Ekberg, J;Kumar, S
通讯作者：
Kumar, S
影响因子：
4.8
作者：
Bhalla, Vivek;Oyster, Nicholas M.;Hallows, Kenneth R.
通讯作者：
Hallows, Kenneth R.
影响因子：
3.3
作者：
Liu, Gong-Lu;Wang, Kai-Yan;Zhao, Yong-Bo
通讯作者：
Zhao, Yong-Bo
HSF1 降解和 UPR 激活的双向相互作用促进 tau 过度磷酸化。
影响因子：
4.5
作者：
Kim E;Sakata K;Liao FF
通讯作者：
Liao FF
影响因子：
16
作者：
Higgins, Renee;Gendron, Joshua M.;Rising, Lisa;Mak, Raymond;Webb, Kristofor;Kaiser, Stephen E.;Zuzow, Nathan;Riviere, Paul;Yang, Bing;Fenech, Emma;Tang, Xin;Lindsay, Scott A.;Christianson, John C.;Hampton, Randolph Y.;Wasserman, Steven A.;Bennett, Eric J.
通讯作者：
Bennett, Eric J.