Molecular Anatomy of Peroxisome Biogenesis and Human Disorders

过氧化物酶体生物发生和人类疾病的分子解剖学

基本信息

批准号：
15207014
负责人：
FUJIKI Yukio
金额：
$ 31.78万
依托单位：
KYUSHU UNIVERCITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2006
项目状态：
已结题

项目摘要

Peroxisomal proteins, including membrane proteins, are encoded by nuclear genes and translated on free polyribosomes in the cytosol. The functional consequence of human peroxisomes is highlighted by fatal genetic peroxisome biogenesis disorders (PBD), including Zellweger syndrome, all of which are linked to a failure of peroxisome assembly. The successful isolation of animal cell mutants prompted us to search for the genes essential for peroxisome assembly. We earlier cloned nine peroxin cDNAs, including PEX1,PEX2 (formerly PAF-1), PEX3,PEX5,PEX6,PEX12,PEX13,PEX14,and PEX19,by functional phenotype- complementation assay on CHO cell mutants; PEX10 and PEX16 by the expressed sequence tag search using yeast genes. We and other groups showed these PEXs to be responsible for human PBD.During the investigation supported by this Grant-in-Aid, we finally succeeded in cloning of a complementing cDNA, PEX26, for a CHO cell mutant ZP167 of the complementation group 8 (CG8,CG-A in Japan). Pex26p, a type-II peroxisomal membrane protein, recruits Pexlp-Pex6p complexes to peroxisomes. We also showed PEX26 is indeed responsible for PBD of CG8. By cloning of PEX26,the mission of search for pathogenic genes for all PBDs has been accomplished. Meanwhile, we recently demonstrated that a mobile shuttling peroxisome targeting signal 1(PTS1)-receptor, Pex5p, carrying the cargos docks with the initial site Pexl4p in a putative import machinery, subsequently translocating to other components such as Pex13p, Pex2p, Pex10p, and Pex12p, using CHO cell mutants, pex2, pex12, pex13, and pex14. Moreover, with regard to peroxisome membrane assembly, we showed that Pex19p functions in the cytosol as a chaperone for membrane proteins and translocates them to peroxisome membrane by docking to Pex3p. Our most recent findings include the regulation of peroxisome morphogenesis. We found that peroxisome morphogenesis is regulated by Pex11p, Fis1, ad DLP1 in a concerted manner.

过氧化物酶体蛋白，包括膜蛋白，由核基因编码，并在细胞质中的游离多核糖体上翻译。人类过氧化物酶体的功能后果由致命的遗传过氧化物酶体生物发生障碍（PBD）突出显示，包括Zellweger综合征，所有这些综合征都与过氧化物酶体组装失败有关。动物细胞突变体的成功分离促使我们寻找过氧化物酶体组装必不可少的基因。我们以前通过功能表型在CHO细胞突变剂上通过功能表型互补测定，以九种过氧蛋白CDNA，包括PEX1，PEX2（以前为PAF-1），PEX3，PEX5，PEX6，PEX1，PEX12，PEX12，PEX13，PEX14和PEX14和PEX19； PEX10和PEX16使用酵母基因的表达序列标签搜索。我们和其他小组表明，这些PEX负责人PBD。在此赠款支持的研究中，我们最终成功地克隆了互补的cDNA PEX26，用于补充组的CHO细胞突变体ZP167（8）（8（ CG8，日本CG-A）。 PEX26P是一种II型过氧化物酶体膜蛋白，将PEXLP-PEX6P复合物募集到过氧化物酶体。我们还显示，PEX26确实负责CG8的PBD。通过克隆PEX26，已经完成了为所有PBD寻找致病基因的使命。同时，我们最近证明了一种移动穿梭的过氧化物酶体靶向信号1（PTS1） - 感受器PEX5P，在推定的进口机械中携带带有初始站点PEXL4P的Cargos码头，随后转化为其他组件，例如PEX13P，PEX13P，PEX2P，PEX2P，PEX110P，和PEX2P，PEX110P，和PEX12P，使用CHO细胞突变体，PEX2，PEX12，PEX13和PEX14。此外，关于过氧化物酶体膜组件，我们表明PEX19P在细胞质中作为膜蛋白的伴侣起作用，并将其转换为PEX3P，将其转移到过氧化物酶体膜上。我们最近的发现包括对过氧化物酶体形态发生的调节。我们发现，过氧化物酶体形态发生受PEX11P，FIS1，AD DLP1的调节，以协同的方式调节。