Department of Cell Biology and Molecular Genetics; University of Maryland; College Park, MD USA.
Nucleus. 2014 Jan-Feb;5(1):66-74. doi: 10.4161/nucl.28068. Epub 2014 Feb 4.
Lamin A is a major component of the lamina, which creates a dynamic network underneath the nuclear envelope. Mutations in the lamin A gene (LMNA) cause severe genetic disorders, one of which is Hutchinson-Gilford progeria syndrome (HGPS), a disease triggered by a dominant mutant named progerin. Unlike the wild-type lamin A, whose farnesylated C-terminus is excised during post-translational processing, progerin retains its farnesyl tail and accumulates on the nuclear membrane, resulting in abnormal nuclear morphology during interphase. In addition, membrane-associated progerin forms visible cytoplasmic aggregates in mitosis. To examine the potential effects of cytoplasmic progerin, nuclear localization signal (NLS) deleted progerin and lamin A (PGΔNLS and LAΔNLS, respectively) have been constructed. We find that both ΔNLS mutants are farnesylated in the cytosol and associate with a sub-domain of the ER via their farnesyl tails. While the farnesylation on LAΔNLS can be gradually removed, which leads to its subsequent release from the ER into the cytoplasm, PGΔNLS remains permanently farnesylated and membrane-bounded. Moreover, both ΔNLS mutants dominantly affect emerin's nuclear localization. These results reveal new insights into lamin A biogenesis and lamin A-emerin interaction.
核纤层蛋白 A 是核纤层的主要成分，它在核膜下形成一个动态网络。核纤层蛋白 A 基因 (LMNA) 的突变会导致严重的遗传疾病，其中一种是亨廷顿病-吉福德早衰综合征（HGPS），这是一种由名为前质蛋白的显性突变体触发的疾病。与野生型核纤层蛋白 A 不同，后者的法尼基化 C 端在翻译后加工过程中被切除，而前质蛋白保留其法尼基尾巴并在核膜上积累，导致间期异常核形态。此外，膜相关的前质蛋白在有丝分裂中形成可见的细胞质聚集。为了研究细胞质前质蛋白的潜在影响，构建了核定位信号（NLS）缺失的前质蛋白和核纤层蛋白 A（PGΔNLS 和 LAΔNLS）。我们发现，这两种 ΔNLS 突变体都在细胞质中被法尼基化，并通过其法尼基尾巴与 ER 的一个亚域结合。虽然 LAΔNLS 上的法尼基化可以逐渐被去除，从而导致其随后从 ER 释放到细胞质中，但 PGΔNLS 仍然被永久法尼基化并与膜结合。此外，这两种 ΔNLS 突变体都主要影响 emerin 的核定位。这些结果为核纤层蛋白 A 的生物发生和核纤层蛋白 A-emerin 相互作用提供了新的见解。
