|Budget Amount *help
¥49,660,000 (Direct Cost: ¥38,200,000、Indirect Cost: ¥11,460,000)
Fiscal Year 2006: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Fiscal Year 2005: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Fiscal Year 2004: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000)
Fiscal Year 2003: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
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.