Biochemie Intrazellulärer Transportprozesse, Ruhr-Universität Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
Int J Mol Sci. 2020 Jan 29;21(3):867. doi: 10.3390/ijms21030867.
The important physiologic role of peroxisomes is shown by the occurrence of peroxisomal biogenesis disorders (PBDs) in humans. This spectrum of autosomal recessive metabolic disorders is characterized by defective peroxisome assembly and impaired peroxisomal functions. PBDs are caused by mutations in the peroxisomal biogenesis factors, which are required for the correct compartmentalization of peroxisomal matrix enzymes. Recent work from patient cells that contain the Pex1(G843D) point mutant suggested that the inhibition of the lysosome, and therefore the block of pexophagy, was beneficial for peroxisomal function. The resulting working model proposed that Pex1 may not be essential for matrix protein import at all, but rather for the prevention of pexophagy. Thus, the observed matrix protein import defect would not be caused by a lack of Pex1 activity, but rather by enhanced removal of peroxisomal membranes via pexophagy. In the present study, we can show that the specific block of deletion-induced pexophagy does not restore peroxisomal matrix protein import or the peroxisomal function in beta-oxidation in yeast. Therefore, we conclude that Pex1 is directly and essentially involved in peroxisomal matrix protein import, and that the deletion-induced pexophagy is not responsible for the defect in peroxisomal function. In order to point out the conserved mechanism, we discuss our findings in the context of the working models of peroxisomal biogenesis and pexophagy in yeasts and mammals.
过氧化物酶体的重要生理功能表现在人类过氧化物酶体生物发生障碍（PBD）的发生。这种常染色体隐性代谢障碍谱的特征是过氧化物酶体组装缺陷和过氧化物酶体功能受损。PBD 是由过氧化物酶体生物发生因子的突变引起的，这些因子是过氧化物酶体基质酶正确区室化所必需的。来自含有 Pex1(G843D)点突变体的患者细胞的最新研究表明，溶酶体的抑制，因此 pexophagy 的阻断，对过氧化物酶体功能是有益的。由此提出的工作模型表明，Pex1 可能根本不是基质蛋白输入所必需的，而是防止 pexophagy。因此，观察到的基质蛋白输入缺陷不是由于 Pex1 活性的缺乏，而是由于通过 pexophagy 增强了过氧化物酶体膜的去除。在本研究中，我们可以证明，特异性阻断诱导的 pexophagy 并不能恢复酵母中过氧化物酶体基质蛋白的输入或β-氧化中的过氧化物酶体功能。因此，我们得出结论，Pex1 直接且本质上参与过氧化物酶体基质蛋白的输入，而诱导的 pexophagy 不是过氧化物酶体功能缺陷的原因。为了指出保守的机制，我们在酵母和哺乳动物过氧化物酶体生物发生和 pexophagy 的工作模型的背景下讨论我们的发现。
