Dynamic quality control machinery that operates across compartmental borders mediates the degradation of mammalian nuclear membrane proteins.
Dynamic quality control machinery that operates across compartmental borders mediates the degradation of mammalian nuclear membrane proteins.
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DOI：
10.1016/j.celrep.2022.111675
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发表时间：
2022-11-22
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
许多人类疾病是由核膜（NE）蛋白突变引起的。蛋白质内稳态和疾病病因如何在NE相互联系还知之甚少。具体而言，促进泛素-蛋白酶体依赖性NE蛋白周转的局部泛素连接酶的身份目前尚不清楚。在这里，我们采用了一个短暂的，核纤层蛋白B受体疾病的变异作为一个模型基板在遗传筛选，以揭示NE蛋白营业额的关键要素。我们确定了泛素结合酶（E2 s）Ube 2G 2和Ube 2D 3，膜驻留泛素连接酶（E3 s）RNF 5和HRD 1，以及知之甚少的蛋白质TMEM 33。RNF 5（而不是HRD 1）需要TMEM 33才能有效生物合成和发挥功能。一旦合成，RNF 5通过离开内质网而动态地响应NE处增加的底物水平，其中HRD 1保持受限。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进行分区，以解决局部变化的底物负荷，从而建立稳健的细胞质量控制系统。核膜蛋白的突变导致许多人类疾病。虽然其中一些影响蛋白质的稳定性，在哺乳动物核膜蛋白质质量控制的机制仍有待阐明。使用功能基因组方法，Tsai等人鉴定了靶向错误折叠的核膜蛋白降解的动态机制。
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. Mutations in nuclear membrane proteins cause many human diseases. While several of those affect protein stability, the mechanisms of protein quality control at the mammalian nuclear envelope remain to be elucidated. Using a functional genomic approach, Tsai et al. identify a dynamic machinery that targets misfolded nuclear membrane proteins for degradation.
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影响因子：
3.3
作者：
Casey AK;Chen S;Novick P;Ferro-Novick S;Wente SR
通讯作者：
Wente SR
通过破坏的顺序：与ER相关的蛋白质降解如何有助于细胞器稳态。
DOI：
10.15252/embj.2021109845
发表时间：
2022-03-15
期刊：
The EMBO journal
影响因子：
--
作者：
Christianson JC;Carvalho P
通讯作者：
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影响因子：
16.6
作者：
Feng S;Sekine S;Pessino V;Li H;Leonetti MD;Huang B
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Huang B
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
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Root DE
影响因子：
14.9
作者：
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通讯作者：
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