González-Granado Jose M, Navarro-Puche Ana, Molina-Sanchez Pedro, Blanco-Berrocal Marta, Viana Rosa, Font de Mora Jaime, Andrés Vicente
Department of Atherothrombosis, Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Instituto de Biomedicina de Valencia (IBV), Consejo Superior de Investigaciones Científicas, Valencia, Spain.
PLoS One. 2014 Dec 23;9(12):e115571. doi: 10.1371/journal.pone.0115571. eCollection 2014.
Nuclear lamins are important structural and functional proteins in mammalian cells, but little is known about the mechanisms and cofactors that regulate their traffic into the nucleus. Here, we demonstrate that trafficking of lamin A, but not lamin B1, and its assembly into the nuclear envelope are regulated by sorting nexin 6 (SNX6), a major component of the retromer that targets proteins and other molecules to specific subcellular locations. SNX6 interacts with lamin A in vitro and in vivo and links it to the outer surface of the endoplasmic reticulum in human and mouse cells. SNX6 transports its lamin A cargo to the nuclear envelope in a process that takes several hours. Lamin A protein levels in the nucleus augment or decrease, respectively, upon gain or loss of SNX6 function. We further show that SNX6-dependent lamin A nuclear import occurs across the nuclear pore complex via a RAN-GTP-dependent mechanism. These results identify SNX6 as a key regulator of lamin A synthesis and incorporation into the nuclear envelope.
核纤层蛋白是哺乳动物细胞中重要的结构和功能蛋白，但对于调节其进入细胞核的机制和辅助因子却知之甚少。在此，我们证明核纤层蛋白A（而非核纤层蛋白B1）的运输及其组装入核膜是由分选连接蛋白6（SNX6）调控的，SNX6是逆转录复合物的主要成分，可将蛋白质和其他分子靶向特定亚细胞位置。SNX6在体外和体内均与核纤层蛋白A相互作用，并将其与人和小鼠细胞内质网的外表面相连。SNX6将其核纤层蛋白A货物运输到核膜的过程需要数小时。SNX6功能的获得或丧失分别导致细胞核中核纤层蛋白A的水平升高或降低。我们进一步表明，依赖SNX6的核纤层蛋白A核输入通过依赖RAN - GTP的机制穿过核孔复合体发生。这些结果确定SNX6是核纤层蛋白A合成和并入核膜的关键调节因子。
