PEX1 is essential for the glycosome biogenesis and trypanosomatid parasite survival

Abstract

Trypanosomatid parasites are kinetoplastid protists that compartmentalize glycolytic enzymes in unique peroxisome-related organelles called glycosomes. The heterohexameric AAA-ATPase complex of PEX1-PEX6 is anchored to the peroxisomal membrane and functions in the export of matrix protein import receptor PEX5 from the peroxisomal membrane. Defects in PEX1, PEX6 or their membrane anchor causes dysfunction of peroxisomal matrix protein import cycle. In this study, we identified theTrypanosomaPEX1 orthologue using sequence and structural similarities. Using yeast two-hybrid analysis, we demonstrate thatTbPEX1 can bind toTbPEX6. Endogenously taggedTbPEX1 localizes to glycosomes in theT. bruceiparasites. Depletion of PEX1 gene expression by RNA interference causes lethality to bloodstream form trypanosomes, due to a partial mislocalization of glycosomal enzymes to the cytosol and ATP depletion.TbPEX1 RNAi leads to a selective proteasomal degradation of both matrix protein import receptorsTbPEX5 andTbPEX7. Unlike in yeast, PEX1 depletion did not result in an accumulation of ubiquitinatedTbPEX5 in trypanosomes. As PEX1 turned out to be essential for trypanosomatid parasites, it could provide a suitable drug target for parasitic diseases. The results also suggests that these parasites possess a highly efficient quality control mechanisms that export the import receptors from glycosomes to the cytosol, in the absence of a functionalTbPEX1-TbPEX6 complex.