The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA ATPase complexes to peroxisomes

Peroxisomes are ubiquitous organelles with a single membrane that contain over 50 different enzymes that catalyse various metabolic pathways, including β-oxidation and lipid synthesis¹. Peroxisome biogenesis disorders (PBDs), such as Zellweger syndrome and neonatal adrenoleukodystrophy, are fatal genetic diseases that are autosomal recessive^2,3 . Among the PBDs of the 12 complementation groups (CGs)⁴, 11 associated PEX genes have been isolated^4-7 . Accordingly, only the PBD pathogenic gene for CG8 (also called CG-A) remains unidentified. Here we have isolated human PEX26 encoding a type II peroxisomal membrane protein of relative molecular mass 34,000 (M_r 34K) by using ZP167 cells, a Chinese hamster ovary (CHO) mutant cell line^5,8. Expression of PEX26 restores peroxisomal protein import in the fibroblasts of an individual with PBD of CG8. This individual possesses a homozygous, inactivating pathogenic point mutation, Arg98Trp, in Pex26. Pex6 and Pex1 of the AAA ATPase family co-immunoprecipitate with Pex26. Epitopetagged Pex6 and Pex1 are discernible as puncta in normal CHO-K1 cells, but not in PEX26-defective cells. PEX26 expression in ZP167 cells re-establishes colocalization of Pex6 and Pex1 with Pex26, in a Pex6-dependent manner. Thus, Pex26 recruits Pex6-Pex1 complexes to peroxisomes.