Laboratoire du Stress et Pathologies du Cytosquelette, Université Paris Diderot-Paris 7, CNRS, Institut de Biologie Fonctionnelle et Adaptative, 4 rue M.A. Lagroua Weill Halle, 75205 Paris cedex 13, France.
Exp Cell Res. 2011 Dec 10;317(20):2800-13. doi: 10.1016/j.yexcr.2011.09.012. Epub 2011 Oct 4.
Lamins A and C are nuclear intermediate filament proteins expressed in most differentiated somatic cells. Previous data suggested that prelamin A, the lamin A precursor, accumulates in some lipodystrophy syndromes caused by mutations in the lamin A/C gene, and binds and inactivates the sterol regulatory element binding protein 1 (SREBP1). Here we show that, in vitro, the tail regions of prelamin A, lamin A and lamin C bind a polypeptide of SREBP1. Such interactions also occur in HeLa cells, since expression of lamin tail regions impedes nucleolar accumulation of the SREBP1 polypeptide fused to a nucleolar localization signal sequence. In addition, the tail regions of A-type lamin variants that occur in Dunnigan-type familial partial lipodystrophy of (R482W) and Hutchison Gilford progeria syndrome (∆607-656) bind to the SREBP1 polypeptide in vitro, and the corresponding FLAG-tagged full-length lamin variants co-immunoprecipitate the SREBP1 polypeptide in cells. Overexpression of wild-type A-type lamins and variants favors SREBP1 polypeptide localization at the intranuclear periphery, suggesting its sequestration. Our data support the hypothesis that variation of A-type lamin protein level and spatial organization, in particular due to disease-linked mutations, influences the sequestration of SREBP1 at the nuclear envelope and thus contributes to the regulation of SREBP1 function.
核纤层蛋白 A 和 C 是大多数分化体细胞中表达的核中间丝蛋白。先前的数据表明，前核纤层蛋白 A（核纤层蛋白 A 的前体）在由核纤层蛋白 A/C 基因突变引起的一些脂肪营养不良综合征中积累，并结合并失活固醇调节元件结合蛋白 1（SREBP1）。在这里，我们表明，在体外，前核纤层蛋白 A、核纤层蛋白 A 和核纤层蛋白 C 的尾部区域与 SREBP1 的多肽结合。这种相互作用也发生在 HeLa 细胞中，因为核纤层尾部区域的表达会阻碍与核仁定位信号序列融合的 SREBP1 多肽在核仁中的积累。此外，在 Dunnigan 型家族性部分脂肪营养不良（R482W）和 Hutchison-Gilford 早衰综合征（∆607-656）中发生的 A 型核纤层变体的尾部区域在体外与 SREBP1 多肽结合，并且相应的 FLAG 标记全长核纤层变体在细胞中共免疫沉淀 SREBP1 多肽。野生型 A 型核纤层蛋白和变体的过表达有利于 SREBP1 多肽在核内周缘的定位，表明其被隔离。我们的数据支持这样一种假设，即 A 型核纤层蛋白水平和空间组织的变化，特别是由于与疾病相关的突变，影响 SREBP1 在核膜上的隔离，从而有助于 SREBP1 功能的调节。
