Pex11p is a peroxin of the inner surface of the peroxisomal membrane and is required for peroxisome biogenesis (9, 6). Peroxisomes perform many essential functions in eukaryotic cells, and divide by budding from preexisting peroxisomes, a process that is not yet understood at the molecular level (4).

PEX11 proteins are widely conserved among eukaryotes, in which they are unique in their ability to promote peroxisome division (10, 11). Peroxisomal proliferation can be induced in S. cerevisiae by oleate, as PEX11 expression is regulated by oleate (4). The PEX11 promoter contains an oleate responsive element (ORE) overlapping a UAS1-like element, and it has been suggested that these elements in conjunction with their binding factors Pip2p-Oaf1p and Adr1p coordinate the carbon flux through beta-oxidation with peroxisome proliferation. Up-regulation of PEX11 is abolished in cells lacking Adr1p (6).

Pex11p in S. cerevisiae plays a primary role in medium-chain fatty acid beta-oxidation, a process that affects peroxisome number and size. Pex11p-deficient cells fail to increase peroxisome number in response to growth on fatty acids and instead accumulate a few giant peroxisomes. Mutants deficient in genes required for medium-chain fatty acid (MCFA) beta-oxidation display the same phenotype as Pex11p-deficient cells. The sole S. cerevisiae MCFA-CoA synthetase (Faa2p) remains properly localized to the inner leaflet of the peroxisomal membrane in PEX11 mutant cells. Therefore, the latency of MCFA activation observed in Pex11p-deficient cells suggests that Pex11p provides Faa2p with substrate. When PEX11 mutant cells are shifted from glucose to oleate-containing medium, an immediate deficiency in beta-oxidation of MCFAs occurs whereas giant peroxisomes and a failure to increase peroxisome abundance only became apparent much later (5).

Cells with a disrupted PEX11 gene grow well on glucose or ethanol, but fail to grow on oleate although peroxisomes were still induced by transfer to oleate-containing medium. The induced peroxisomes of pex11delta cells are fewer but considerably larger than wild-type. pex11delta cells cultured in oleate-containing medium form multiple buds, most of which are peroxisome-deficient. The growth defect of pex11delta cells on oleic acid appears to result from the inability to segregate the giant peroxisomes to daughter cells (3).

Pex25p and Pex27p have C-termini which are similar to the entire Pex11p, and localize to the peroxisomal membrane. Deletion of PEX25 or PEX27 also results in enlarged peroxisomes. A partial growth defect on fatty acids of a pex25delta mutant is not exacerbated by the additional deletion of PEX27; however, when PEX11 is also deleted, growth is abolished on all fatty acids. Moreover, the triple mutant strain exhibits a severe peroxisomal protein import defect (12). Overexpression of PEX27 or PEX25 leads to peroxisome proliferation and the formation of small peroxisomes. Overexpression of PEX11 has been reported to produce this same small-peroxisome phenotype (13), and also a similar phenotype in which cells contain an increased number of normal-sized peroxisomes (4).

Human have three PEX11 homologs - PEX11alpha, -beta, and -gamma - and PEX11 deficiencies in humans have been implicated in Zellweger syndrome, a lethal neurological disorder characterized by severe defects in peroxisomal protein import. The resulting defects in peroxisome metabolism and the accumulation of peroxisomal substrates are thought to cause the other Zellweger syndrome phenotypes, including neuronal migration defects, hypotonia, developmental delay, and neonatal lethality (14, 15).

Last updated: 2005-03-03