Gene expression modulation by the linker of nucleoskeleton and cytoskeleton complex contributes to proteostasis.,Aging Cell

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Gene expression modulation by the linker of nucleoskeleton and cytoskeleton complex contributes to proteostasis.
Aging Cell ( IF 8.0 ) Pub Date : 2019-10-01 , DOI: 10.1111/acel.13047
Amir Levine ₁ , Danielle Grushko ₁ , Ehud Cohen ₁

Affiliation

Cellular mechanisms that act in concert to maintain protein homeostasis (proteostasis) are vital for organismal functionality and survival. Nevertheless, subsets of aggregation‐prone proteins form toxic aggregates (proteotoxicity) that in some cases, underlie the development of neurodegenerative diseases. Proteotoxic aggregates are often deposited in the vicinity of the nucleus, a process that is cytoskeleton‐dependent. Accordingly, cytoskeletal dysfunction contributes to pathological hallmarks of various neurodegenerative diseases. Here, we asked whether the linker of nucleoskeleton and cytoskeleton (LINC) complex, which bridges these filaments across the nuclear envelope, is needed for the maintenance of proteostasis. Employing model nematodes, we discovered that knocking down LINC components impairs the ability of the worm to cope with proteotoxicity. Knocking down anc‐1, which encodes a key component of the LINC complex, modulates the expression of transcription factors and E3 ubiquitin ligases, thereby affecting the rates of protein ubiquitination and impairing proteasome‐mediated protein degradation. Our results establish a link between the LINC complex, protein degradation, and neurodegeneration‐associated proteotoxicity.

中文翻译：

核骨架和细胞骨架复合物的连接子对基因表达的调节有助于蛋白稳态。

协同作用以维持蛋白质稳态（蛋白稳态）的细胞机制对于机体功能和生存至关重要。但是，易于聚集的蛋白质的子集会形成有毒的聚集体（蛋白毒性），在某些情况下是神经退行性疾病发展的基础。蛋白毒性聚集物通常沉积在细胞核附近，该过程是细胞骨架依赖性的。因此，细胞骨架功能障碍是各种神经退行性疾病的病理学标志。在这里，我们询问是否需要维持这些丝穿过核被膜的核骨架和细胞骨架（LINC）复合物的连接子来维持蛋白稳态。使用模型线虫，我们发现敲除LINC组件会损害蠕虫应对蛋白毒性的能力。撞倒编码LINC复合体关键成分的anc-1调节转录因子和E3泛素连接酶的表达，从而影响蛋白质泛素化的速率并削弱蛋白酶体介导的蛋白质降解。我们的结果在LINC复合物，蛋白质降解和神经退行性蛋白毒性之间建立了联系。

更新日期：2019-10-01

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