Chang C C, South S, Warren D, Jones J, Moser A B, Moser H W, Gould S J
The Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
J Cell Sci. 1999 May;112 ( Pt 10):1579-90. doi: 10.1242/jcs.112.10.1579.
Zellweger syndrome and related disorders represent a group of lethal, genetically heterogeneous diseases. These peroxisome biogenesis disorders (PBDs) are characterized by defective peroxisomal matrix protein import and comprise at least 10 complementation groups. The genes defective in seven of these groups and more than 90% of PBD patients are now known. Here we examine the distribution of peroxisomal membrane proteins in fibroblasts from PBD patients representing the seven complementation groups for which the mutant gene is known. Peroxisomes were detected in all PBD cells, indicating that the ability to form a minimal peroxisomal structure is not blocked in these mutants. We also observed that peroxisome abundance was reduced fivefold in PBD cells that are defective in the PEX1, PEX5, PEX12, PEX6, PEX10, and PEX2 genes. These cell lines all display a defect in the import of proteins with the type-1 peroxisomal targeting signal (PTS1). In contrast, peroxisome abundance was unaffected in cells that are mutated in PEX7 and are defective only in the import of proteins with the type-2 peroxisomal targeting signal. Interestingly, a fivefold reduction in peroxisome abundance was also observed for cells lacking either of two PTS1-targeted peroxisomal beta-oxidation enzymes, acyl-CoA oxidase and 2-enoyl-CoA hydratase/D-3-hydroxyacyl-CoA dehydrogenase. These results indicate that reduced peroxisome abundance in PBD cells may be caused by their inability to import these PTS1-containing enzymes. Furthermore, the fact that peroxisome abundance is influenced by peroxisomal 105-oxidation activities suggests that there may be metabolic control of peroxisome abundance.
泽韦格综合征及相关疾病是一组致命的、基因异质性疾病。这些过氧化物酶体生物发生障碍（PBDs）的特征是过氧化物酶体基质蛋白导入缺陷，至少包括10个互补组。目前已知道其中7个组以及超过90%的PBD患者中存在缺陷的基因。在这里，我们研究了代表已知突变基因的7个互补组的PBD患者成纤维细胞中过氧化物酶体膜蛋白的分布。在所有PBD细胞中都检测到了过氧化物酶体，这表明在这些突变体中形成最小过氧化物酶体结构的能力并未被阻断。我们还观察到，在PEX1、PEX5、PEX12、PEX6、PEX10和PEX2基因存在缺陷的PBD细胞中，过氧化物酶体丰度降低了五倍。这些细胞系均显示出具有1型过氧化物酶体靶向信号（PTS1）的蛋白导入存在缺陷。相比之下，在PEX7发生突变且仅在具有2型过氧化物酶体靶向信号的蛋白导入方面存在缺陷的细胞中，过氧化物酶体丰度未受影响。有趣的是，对于缺乏两种靶向PTS1的过氧化物酶体β氧化酶（酰基辅酶A氧化酶和2-烯酰基辅酶A水合酶/D-3-羟酰基辅酶A脱氢酶）中任何一种的细胞，也观察到过氧化物酶体丰度降低了五倍。这些结果表明，PBD细胞中过氧化物酶体丰度降低可能是由于它们无法导入这些含PTS1的酶所致。此外，过氧化物酶体丰度受105-氧化过氧化物酶体活性影响这一事实表明，可能存在对过氧化物酶体丰度的代谢控制。
