Laminopathy-inducing lamin A mutants can induce redistribution of lamin binding proteins into nuclear aggregates
Laminopathy-inducing lamin A mutants can induce redistribution of lamin binding proteins into nuclear aggregates
复制标题
DOI：
10.1016/j.yexcr.2005.10.011
复制
发表时间：
2005-01-15
影响因子：
3.7
通讯作者：
Jans, DA
中科院分区：
文献类型：
--
作者：
Hübner, S;Eam, JE;Jans, DA
层粘连蛋白是中间丝家族的成员，在核膜下形成一个支持性的核骨架结构，也可以形成核内结构。A型层粘连蛋白基因的突变会导致多种退行性疾病，统称为椎板病。在分子水平上，已经证明椎板病与A型椎板的不连续定位模式有关，一些椎板病含有核层粘连蛋白A聚集体。由于核聚集体的形成可能导致与A型Lamins相互作用的蛋白质的错位定位，我们开始研究FLAG-lamin A N195K和R386K蛋白质聚集体的形成对作为GH融合蛋白在HeLa细胞中共表达后视网膜母细胞瘤蛋白(PRB)和类固醇反应元件结合蛋白1a(SREBPla)亚核分布的影响。我们观察到这两种蛋白质都强烈地聚集到核聚集体中。还观察到鼻咽癌成分核孔蛋白Nup 153的核聚集募集，并发现其依赖于N-末端。这些效应是特异的，因为许多其他共表达的亲核GFP融合蛋白，如核孔蛋白NUP98和KanAdaptin，不与FLAG-lamin A N195K或R386K共同聚集。免疫荧光分析进一步表明，在核内聚集体中可以发现层蛋白A的前体形式，即层蛋白A的前体。我们的结果表明，PRB和SREBPIa等蛋白质重新分布到含有Lamin A-/Pre-laniin A的聚合体中可能是某些椎板病分子发病机制的一个关键方面。(C)2005 Elsevier Inc.保留所有权利。
Lamins, members of the family of intermediate filaments, form a supportive nucleoskeletal structure underlying the nuclearenvelope and can also form intranuclear structures. Mutations within the A-type lamin gene cause a variety of degenerative diseases which are collectively referred to as laminopathies. At the molecular level, laminopathies have been shown to be linked to a discontinuous localization pattern of A-type lamins, with some laminopathies containing nuclear lamin A aggregates. Since nuclear aggregate formation could lead to the mislocalization of proteins interacting with A-type lamins, we set out to examine the effects of FLAG-lamin A N195K and R386K protein aggregate formation on the subnuclear distribution of the retinoblastoma protein (pRb) and the sterol responsive element binding protein 1a (SREBPla) after coexpression as GH-fusion proteins in HeLa cells. We observed strong recruitment of both proteins into nuclear aggregates. Nuclear aggregate recruitment of the NPC component nucleoporin NUP 153 was also observed and found to be dependent on the N-terminus. That these effects were specific was implied by the fact that a number of other coexpressed karyophilic GFP-fusion proteins, Such as the nucleoporin NUP98 and kanadaptin, did not coaggregate with FLAG-lamin A N195K or R386K. Immunoflourescence analysis further indicated that the precursor form of lamin A, pre-lamin A, Could be found in intranuclear aggregates. Our results imply that redistribution into lamin A-/pre-laniin A-containing aggregates of proteins such as pRb and SREBPIa could represent a key aspect underlying the molecular pathogenesis of certain laminopathies. (c) 2005 Elsevier Inc. All rights reserved.