Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance
Failure of microtubule-mediated peroxisome division and trafficking in disorders with reduced peroxisome abundance
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DOI：
10.1242/jcs.02776
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发表时间：
2006-02-15
影响因子：
4
通讯作者：
Crane, DI
中科院分区：
文献类型：
--
作者：
Nguyen, T;Bjorkman, J;Crane, DI
与正常细胞中的过氧化物体相比，临床上严重的过氧素体疾病的一部分，包括生物发生障碍Zellweger综合征和单酶缺陷D-双功能蛋白(D-BP)缺乏症，培养的皮肤成纤维细胞中残留的过氧酶体变大，且含量明显减少。我们测试了这些特征是否与微管在哺乳动物细胞中过氧化物体运输中的已知作用有关。我们发现，PEX1缺失的Zellweger综合征或D-BP缺乏症患者成纤维细胞中残留的过氧化物酶体沿外周微管呈聚集和排列丢失。对于培养的胚胎成纤维细胞和来自具有Zellweger综合征样表型的PEX13缺失小鼠的脑神经元，也观察到了类似的影响，而来自一名PEX1突变较轻微纯合的婴儿Refsum患者的成纤维细胞的影响则不那么明显。相比之下，在过氧化物酶体丰度和大小正常的过氧酶体紊乱患者中则没有看到这种变化。PEX11β的稳定过表达诱导了过氧化物酶体的增殖，在PEX1缺失和D-BP缺陷的细胞中，很大程度上重建了沿着外周微管的过氧化物体结构的排列。在D-BP缺失的细胞中，由于诱导的过氧化体结构类似于球形亲本结构，因此过氧化体分裂明显被驱动到完成。相比之下，在PEX1缺失的细胞中，大多数诱导的过氧化体结构是细长的和管状的。这些结构显然是在分裂步骤中被阻止的，尽管已经招募了DLP1，这是一种过氧化酶体分裂所必需的蛋白质。这些发现表明，在PEX1缺失和D-BP缺陷的细胞中，过氧化体结构的大小增加、丰度降低和胞质分布紊乱，反映了过氧化物体增殖和分裂的不同阶段的缺陷，这些过程需要这些结构与微管结合并沿微管扩散。
In contrast to peroxisomes in normal cells, remnant peroxisomes in cultured skin fibroblasts from a subset of the clinically severe peroxisomal disorders that includes the biogenesis disorder Zellweger syndrome and the single-enzyme defect D-bifunctional protein (D-BP) deficiency, are enlarged and significantly less abundant. We tested whether these features could be related to the known role of microtubules in peroxisome trafficking in mammalian cells. We found that remnant peroxisomes in fibroblasts from patients with PEX1-null Zellweger syndrome or D-BP deficiency exhibited clustering and loss of alignment along peripheral microtubules. Similar effects were observed for both cultured embryonic fibroblasts and brain neurons from a PEX13-null mouse with a Zellweger-syndrome-like phenotype, and a less-pronounced effect was observed for fibroblasts from an infantile Refsum patient who was homozygous for a milder PEX1 mutation. By contrast, such changes were not seen for patients with peroxisomal disorders characterized by normal peroxisome abundance and size. Stable overexpression of PEX11 beta to induce peroxisome proliferation largely re-established the alignment of peroxisomal structures along peripheral microtubules in both PEX1-null and D-BP-deficient cells. In D-BP-deficient cells, peroxisome division was apparently driven to completion, as induced peroxisomal structures were similar to the spherical parental structures. By contrast, in PEX1-null cells the majority of induced peroxisomal structures were elongated and tubular. These structures were apparently blocked at the division step, despite having recruited DLP1, a protein necessary for peroxisome fission. These findings indicate that the increased size, reduced abundance, and disturbed cytoplasmic distribution of peroxisomal structures in PEX1-null and D-BP-deficient cells reflect defects at different stages in peroxisome proliferation and division, processes that require association of these structures with, and dispersal along, microtubules.