A protein quality control pathway regulated by linear ubiquitination
A protein quality control pathway regulated by linear ubiquitination
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DOI：
10.15252/embj.2018100730
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发表时间：
2019-05-02
期刊：
影响因子：
11.4
通讯作者：
Winklhofer, Konstanze F.
中科院分区：
文献类型：
--
作者：
van Well, Eva M.;Bader, Verian;Winklhofer, Konstanze F.
神经退行性疾病的特征在于错误折叠的蛋白质在脑中的积累。深入了解蛋白质质量控制机制，以防止神经元功能障碍和细胞死亡是至关重要的因果疗法的发展。在这里，我们报告，各种疾病相关的蛋白质聚集体的线性泛素链组装复合物（LUBAC）的修改。HOIP是LUBAC的催化组分，以p97/VCP依赖性方式被募集到错误折叠的亨廷顿蛋白，导致线性聚泛素的组装。因此，错误折叠的亨廷顿蛋白种类的相互作用表面被屏蔽而不受不需要的相互作用，例如与含有低复杂性序列结构域的转录因子Sp1的相互作用，并且促进了错误折叠的亨廷顿蛋白的蛋白酶体降解。值得注意的是，所有三个核心LUBAC组分都受Sp1的转录调控，将LUBAC表达缺陷与亨廷顿病联系起来。为了支持线性泛素化的保护活性，OTULIN（一种对线性多聚泛素具有独特特异性的去泛素化酶）的沉默降低了蛋白毒性，而HOIP的沉默具有相反的作用。这些发现将线性泛素化确定为蛋白质质量控制机制，因此是蛋白质病中疾病修饰策略的新靶点。
Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.