Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City, Mexico.
Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City, Mexico; Laboratory of Protein Dynamics and Signaling, Center for Cancer Research-Frederick, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
Biochim Biophys Acta Mol Cell Res. 2018 Feb;1865(2):406-420. doi: 10.1016/j.bbamcr.2017.11.013. Epub 2017 Nov 21.
β-Dystroglycan (β-DG) is a plasma membrane protein that has ability to target to the nuclear envelope (NE) to maintain nuclear architecture. Nevertheless, mechanisms controlling β-DG nuclear localization and the physiological consequences of a failure of trafficking are largely unknown. We show that β-DG has a nuclear export pathway in myoblasts that depends on the recognition of a nuclear export signal located in its transmembrane domain, by CRM1. Remarkably, NES mutations forced β-DG nuclear accumulation resulting in mislocalization and decreased levels of emerin and lamin B1 and disruption of various nuclear processes in which emerin (centrosome-nucleus linkage and β-catenin transcriptional activity) and lamin B1 (cell cycle progression and nucleoli structure) are critically involved. In addition to nuclear export, the lifespan of nuclear β-DG is restricted by its nuclear proteasomal degradation. Collectively our data show that control of nuclear β-DG content by the combination of CRM1 nuclear export and nuclear proteasome pathways is physiologically relevant to preserve proper NE structure and activity.
β-肌联蛋白（β-DG）是一种位于细胞质膜的蛋白，它具有靶向核膜（NE）的能力，以维持核的结构。然而，控制β-DG 核定位的机制以及运输失败的生理后果在很大程度上仍是未知的。我们发现肌母细胞中存在β-DG 的核输出途径，该途径依赖于 CRM1 识别其跨膜结构域中的核输出信号。值得注意的是，NES 突变迫使β-DG 核积累，导致其定位错误，同时导致 emerin 和 lamin B1 的水平降低，并破坏了 emerin（中心体-核连接和β-连环蛋白转录活性）和 lamin B1（细胞周期进程和核仁结构）等多种核过程。除了核输出外，核β-DG 的寿命还受到核蛋白酶体降解的限制。总的来说，我们的数据表明，CRM1 核输出和核蛋白酶体途径共同控制核β-DG 的含量，这对于维持适当的 NE 结构和功能具有生理相关性。
