National Research Council of Italy, Institute of Molecular Genetics, IGM-CNR, Unit of Bologna c/o IOR, Via di Barbiano 1/10, I-40136 Bologna, Italy.
Biochem Soc Trans. 2011 Dec;39(6):1698-704. doi: 10.1042/BST20110657.
Prelamin A is the precursor protein of lamin A, a major constituent of the nuclear lamina in higher eukaryotes. Increasing attention to prelamin A processing and function has been given after the discovery, from 2002 to 2004, of diseases caused by prelamin A accumulation. These diseases, belonging to the group of laminopathies and mostly featuring LMNA mutations, are characterized, at the clinical level, by different degrees of accelerated aging, and adipose tissue, skin and bone abnormalities. The outcome of studies conducted in the last few years consists of three major findings. First, prelamin A is processed at different rates under physiological conditions depending on the differentiation state of the cell. This means that, for instance, in muscle cells, prelamin A itself plays a biological role, besides production of mature lamin A. Secondly, prelamin A post-translational modifications give rise to different processing intermediates, which elicit different effects in the nucleus, mostly by modification of the chromatin arrangement. Thirdly, there is a threshold of toxicity, especially of the farnesylated form of prelamin A, whose accumulation is obviously linked to cell and organism senescence. The present review is focused on prelamin A-mediated nuclear envelope modifications that are upstream of chromatin dynamics and gene expression mechanisms regulated by the lamin A precursor.
早老素 A 是核纤层蛋白 A 的前体蛋白，核纤层蛋白 A 是高等真核生物核纤层的主要组成部分。自 2002 年至 2004 年发现早老素 A 积累会导致疾病以来，人们对早老素 A 的加工和功能给予了越来越多的关注。这些疾病属于核纤层病组，大多表现为 LMNA 突变，其临床特征是不同程度的加速衰老，以及脂肪组织、皮肤和骨骼异常。在过去几年中进行的研究得出了三个主要发现。首先，早老素 A 在不同的生理条件下以不同的速度进行加工，这取决于细胞的分化状态。这意味着，例如，在肌肉细胞中，早老素 A 本身除了产生成熟的核纤层蛋白 A 之外，还具有生物学作用。其次，早老素 A 的翻译后修饰产生不同的加工中间产物，这些中间产物通过修饰染色质排列在核内产生不同的效应。第三，存在毒性阈值，尤其是早老素 A 的法尼基化形式，其积累显然与细胞和生物体衰老有关。本综述重点介绍了早老素 A 介导的核膜修饰，这些修饰位于染色质动力学和由核纤层蛋白 A 前体调节的基因表达机制的上游。
