PDF(Pubmed)
Abstract：
Many human diseases are caused by mutations in nuclear envelope (NE) proteins. How protein homeostasis and disease etiology are interconnected at the NE is poorly understood. Specifically, the identity of local ubiquitin ligases that facilitate ubiquitin-proteasome-dependent NE protein turnover is presently unknown. Here, we employ a short-lived, Lamin B receptor disease variant as a model substrate in a genetic screen to uncover key elements of NE protein turnover. We identify the ubiquitin-conjugating enzymes (E2s) Ube2G2 and Ube2D3, the membrane-resident ubiquitin ligases (E3s) RNF5 and HRD1, and the poorly understood protein TMEM33. RNF5, but not HRD1, requires TMEM33 both for efficient biosynthesis and function. Once synthesized, RNF5 responds dynamically to increased substrate levels at the NE by departing from the endoplasmic reticulum, where HRD1 remains confined. Thus, mammalian protein quality control machinery partitions between distinct cellular compartments to address locally changing substrate loads, establishing a robust cellular quality control system.
摘要：
许多人类疾病是由核膜（NE）蛋白的突变引起的。蛋白质稳态和疾病病因在NE上如何相互联系的了解很少。具体来说,目前尚不清楚促进泛素-蛋白酶体依赖性NE蛋白周转的局部泛素连接酶。这里,我们雇佣了一个短暂的，LaminB受体疾病变体作为遗传筛选中的模型底物，以揭示NE蛋白周转的关键要素。我们鉴定了泛素缀合酶（E2s）Ube2G2和Ube2D3，膜驻留的泛素连接酶（E3s）RNF5和HRD1以及对蛋白质TMEM33了解甚少。RNF5,而不是HRD1,需要TMEM33来实现有效的生物合成和功能。一旦合成，RNF5通过离开内质网动态响应NE处增加的底物水平，HRD1仍然受到限制。因此，哺乳动物蛋白质质量控制机制在不同的细胞区室之间划分，以解决局部变化的底物负荷，建立一个强大的细胞质量控制系统。
