Molecular mechanisms of peroxisome assembly

在过去的40年里，临床医生越来越多地认识到一组致命的神经疾病所造成的损失，这些疾病统称为过氧化物酶体生物发生障碍。所有这些疾病都会影响过氧化物体的组装，过氧化物体是降解和生物合成脂质所需的细胞内细胞器。因此，要了解过氧酶体生物发生障碍的基础，我们必须了解细胞中过氧酶体是如何形成的。直到最近，细胞组织的基本原理之一是，过氧化体构成一个单一的细胞器隔室。任何细胞类型或组织中的所有过氧化物体在其蛋白质和脂肪组成、它们输入各种蛋白质或转移脂质物种的能力以及它们的代谢能力方面都是相同的。过氧化物酶体也被认为是一种独立的细胞器，它本身保持着化学成分和功能状态的平衡，不能通过膜封闭的载体与其他细胞器通信。因此，过氧化体组装被认为是结构和功能相同的过氧化体通过翻译后同时输入所有蛋白质和通过大量转移所有膜脂而增大大小的过程。由此产生的过氧化物体种群在结构和功能性质上是一致的，被认为是通过完全组装的过氧化物体的分裂或萌发来复制的。我们实验室最近的工作挑战了这种“教科书”的观点。我们已经证明，细胞的过氧体群体由大的成熟的过氧体和较小的未成熟的过氧体组成。未成熟的过氧酶体通过更不成熟的形式到更成熟的形式的有序和渐进的转换而产生成熟的过氧酶体。我们现在提出的实验旨在阐明控制这一多步过氧化体组装途径的分子机制，涉及到过氧化酶体的形成和逐步成熟。充分了解过氧化物酶体是如何组装的，这是理解过氧化物酶体生物发生障碍的分子基础的基础，并为未来治疗这些疾病的治疗方法奠定了基础。

For the past four decades, clinicians have developed a growing appreciation for the toll exacted by a group of lethal neurological disorders collectively called the peroxisome biogenesis disorders. All these diseases affect the assembly of the peroxisome, an intracellular organelle that is required for the degradation and biosynthesis of lipids. Therefore to understand the bases of the peroxisome biogenesis disorders, we must understand how peroxisomes are made in the cell. Until recently, one of the basic tenets of cellular organization was that the peroxisome constitutes a singular organellar compartment. All peroxisomes in any cell type or tissue were assumed to be identical in terms of their protein and lipid composition, their ability to import various proteins or transfer lipid species, and their metabolic capacity. The peroxisome was also believed to be an autonomous organelle that by itself maintained a balance of its chemical composition and functional status, being unable to communicate with other organelles via membrane-enclosed carriers. Peroxisome assembly was thus seen as a process by which structurally and functionally identical peroxisomes increase in size by the posttranslational import of all proteins at the same time and by the transfer of all membrane lipids in bulk. The resulting peroxisomal population, uniform in terms of its structural and functional properties, was believed to replicate by the fission or budding of fully assembled peroxisomes. Recent work from our laboratory has challenged this "textbook" view. We have shown that the peroxisome population of a cell consists of both large mature peroxisomes and smaller immature peroxisomes. The immature peroxisomes give rise to mature peroxisomes through the ordered and progressive conversion of a more immature form to a more mature form. The experiments that we now propose are aimed at elucidating the molecular mechanisms controlling this multistep peroxisome assembly pathway in regards to peroxisome formation and stepwise maturation. Full knowledge of how peroxisomes assemble is fundamental to understanding the molecular bases of the peroxisome biogenesis disorders and lays the foundation for future therapeutic approaches to the treatment of these diseases.