Key points are not available for this paper at this time.
PEX genes encode proteins (peroxins) that are required for the biogenesis of peroxisomes. One of these peroxins, Pex5p, is the receptor for matrix proteins with a type 1 peroxisomal targeting signal (PTS1), which shuttles newly synthesized proteins from the cytosol into the peroxisome matrix. We observed that in various Saccharomyces cerevisiae pex mutants disturbed in the early stages of PTS1 import, the steady-state levels of Pex5p are enhanced relative to wild type controls. Furthermore, we identified ubiquitinated forms of Pex5p in deletion mutants of those PEX genes that have been implicated in recycling of Pex5p from the peroxisomal membrane into the cytosol. Pex5p ubiquitination required the presence of the ubiquitin-conjugating enzyme Ubc4p and the peroxins that are required during early stages of PTS1 protein import. Finally, we provide evidence that the proteasome is involved in the turnover of Pex5p in wild type yeast cells, a process that requires Ubc4p and occurs at the peroxisomal membrane. Our data suggest that during receptor recycling a portion of Pex5p becomes ubiquitinated and degraded by the proteasome. We propose that this process represents a conserved quality control mechanism in peroxisome biogenesis. PEX genes encode proteins (peroxins) that are required for the biogenesis of peroxisomes. One of these peroxins, Pex5p, is the receptor for matrix proteins with a type 1 peroxisomal targeting signal (PTS1), which shuttles newly synthesized proteins from the cytosol into the peroxisome matrix. We observed that in various Saccharomyces cerevisiae pex mutants disturbed in the early stages of PTS1 import, the steady-state levels of Pex5p are enhanced relative to wild type controls. Furthermore, we identified ubiquitinated forms of Pex5p in deletion mutants of those PEX genes that have been implicated in recycling of Pex5p from the peroxisomal membrane into the cytosol. Pex5p ubiquitination required the presence of the ubiquitin-conjugating enzyme Ubc4p and the peroxins that are required during early stages of PTS1 protein import. Finally, we provide evidence that the proteasome is involved in the turnover of Pex5p in wild type yeast cells, a process that requires Ubc4p and occurs at the peroxisomal membrane. Our data suggest that during receptor recycling a portion of Pex5p becomes ubiquitinated and degraded by the proteasome. We propose that this process represents a conserved quality control mechanism in peroxisome biogenesis. Peroxisomes are vital cell organelles and may contain highly variable sets of enzymes that control many important cellular processes. Their importance is demonstrated by the discovery of a number of inherited human metabolic disorders, with the prototype being Zellweger Syndrome, that have been associated with peroxisomal defects, varying from the non-functioning of a single peroxisomal enzyme to complete absence of the organelle (reviewed in Ref. 1Weller S. Gould S.J. Valle D. Annu. Rev. Genomics Hum. Genet. 2003; 4: 165-211Crossref PubMed Scopus (158) Google Scholar). Peroxisomal enzymes are synthesized in the cytosol and delivered post-translationally to their target organelle. To enable this sorting, these enzymes contain specific peroxisomal targeting signals (PTS), 1The abbreviations used are: PTS, peroxisomal targeting signal; protA, protein A; MALDI, matrix-assisted laser desorption ionization. 1The abbreviations used are: PTS, peroxisomal targeting signal; protA, protein A; MALDI, matrix-assisted laser desorption ionization. most of which fall into two categories (reviewed in Ref. 2Purdue P.E. Lazarow P.B. Annu. Rev. Cell Dev. Biol. 2001; 17: 701-752Crossref PubMed Scopus (285) Google Scholar). The vast majority of proteins contains a signal (PTS1) that is located at the carboxyl terminus and has a consensus sequence related to the canonical -S-K-L-COOH sequence observed in firefly luciferase (3Gould S.J. Keller G.A. Hosken N. Wilkinson J. Subramani S. J. Cell Biol. 1989; 108: 1657-1664Crossref PubMed Scopus (881) Google Scholar). So far, only a few proteins have been discovered that utilize a PTS2 to enter peroxisomes. This signal, first described for rat 3-ketoacyl-CoA thiolase (4Swinkels B.W. Gould S.J. Bodnar A.G. Rachubinski R.A. Subramani S. EMBO J. 1991; 10: 3255-3262Crossref PubMed Scopus (515) Google Scholar), is located at the amino terminus of proteins and has the consensus sequence (R/K)(L/V/I)X5(H/Q)(L/A). Additionally, certain proteins contain neither a PTS1 nor a PTS2, but are sorted via still unidentified signals. Finally, because folded and multimeric proteins are also imported into peroxisomes, an alternative strategy that is used by certain proteins is to hitch-hike into the organelle by binding to a protein containing a PTS (see e.g. Refs. 5Yang X. Purdue P.E. Lazarow P.B. Eur. J. Cell Biol. 2001; 80: 126-138Crossref PubMed Scopus (62) Google Scholar and 6Titorenko V.I. Nicaud J.M. Wang H. Chan H. Rachubinski R.A. J. Cell Biol. 2002; 156: 481-494Crossref PubMed Scopus (105) Google Scholar). For both peroxisomal targeting signals, separate cytosolic receptor molecules have been discovered, Pex5p for the PTS1, and Pex7p for the PTS2 (reviewed in Ref. 2Purdue P.E. Lazarow P.B. Annu. Rev. Cell Dev. Biol. 2001; 17: 701-752Crossref PubMed Scopus (285) Google Scholar), which appear to have a shuttling function. During the receptor cycle, Pex5p binds cargo proteins in the cytosol, sorts these to the surface of the organelle, and, subsequently, assists in transporting them across the membrane in a hitherto unknown fashion. Recent evidence suggests that the PTS1 receptor may actually accompany the cargo protein into the peroxisome, prior to its release into the lumen of the organelle (7Dammai V. Subramani S. Cell. 2001; 105: 187-196Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar). Finally, the receptor is brought back to the cytosol for a new import cycle, a step that has been demonstrated to require ATP hydrolysis (8Oliveira M.E. Gouveia A.M. Pinto R.A. Sa-Miranda C. Azevedo J.E. J. Biol. Chem. 2003; 278: 39483-39488Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Previous investigations have identified a variety of other proteins directly involved in the biogenesis of peroxisomes (termed peroxins; see Ref. 9Distel B. Erdmann R. Gould S.J. Blobel G. Crane D.I. Cregg J.M. Dodt G. Fujiki Y. Goodman J.M. Just W.W. Kiel J.A.K.W. Kunau W.H. Lazarow P.B. Mannaerts G.P. Moser H.W. Osumi T. Rachubinski R.A. Roscher A. Subramani S. Tabak H.F. Tsukamoto T. van der Valle D. Klei I. van Veldhoven P.P. Veenhuis M. J. Cell Biol. 1996; 135: 1-3Crossref PubMed Scopus (313) Google Scholar; reviewed in Ref. 2Purdue P.E. Lazarow P.B. Annu. Rev. Cell Dev. Biol. 2001; 17: 701-752Crossref PubMed Scopus (285) Google Scholar). Based on these data, specific peroxins have been suggested to function at distinct steps during peroxisome biogenesis (cf. 10Collins C.S. Kalish J.E. Morrell J.C. McCaffery J.M. Gould S.J. Mol. Cell. Biol. 2000; 20: 7516-7526Crossref PubMed Scopus (136) Google Scholar). Peroxins that are required for the formation/maintenance of the peroxisomal membrane are Pex3p and Pex19p (11Hettema E.H. van den Girzalsky W. Berg M. Erdmann R. Distel B. EMBO J. 2000; 19: 223-233Crossref PubMed Scopus (223) Google Scholar). Furthermore, a docking/translocation complex at the peroxisomal membrane has been proposed that initiates binding of cargo-loaded Pex5p molecules and, subsequently, facilitates translocation of the cargo into the peroxisomal matrix (1Weller S. Gould S.J. Valle D. Annu. Rev. Genomics Hum. Genet. 2003; 4: 165-211Crossref PubMed Scopus (158) Google Scholar, 2Purdue P.E. Lazarow P.B. Annu. Rev. Cell Dev. Biol. 2001; 17: 701-752Crossref PubMed Scopus (285) Google Scholar). This large complex has been shown to consist of two subcomplexes: a docking complex, comprising Pex13p, Pex14p, and Pex17p, and a putative translocation complex consisting of Pex2p, Pex10p, and Pex12p. These complexes are presumed to be held together by protein-protein interactions via the peroxins Pex3p P.P. I. Subramani S. 2002; PubMed Scopus Google Scholar, B. H. A. Girzalsky W. Kunau W.H. Mol. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The which has only been discovered in yeast also to have a in matrix protein import by cargo from Pex5p molecules A. Girzalsky W. T. Distel B. Veenhuis M. Kunau W.H. Erdmann R. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, D. van der Veenhuis M. Klei J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). Finally, a number of proteins have been suggested to a in recycling of the receptor to the cytosol. These two of the and Saccharomyces these are to the peroxisomal membrane by a and the peroxisomal membrane protein (see Refs. I. van den Berg M. A. Kunau W.H. Tabak H.F. Mol. Biol. Cell. 2003; PubMed Scopus (105) Google Scholar and a protein only related to which to a function N. S. Fujiki Y. Cell Biol. 2003; PubMed Scopus Google Scholar). Additionally, two peroxins that have only been in yeast the ubiquitin-conjugating enzyme and the membrane protein A. Keller G.A. Subramani S. J. Cell Biol. PubMed Google Scholar), are to a in Pex5p recycling C.S. Kalish J.E. Morrell J.C. McCaffery J.M. Gould S.J. Mol. Cell. Biol. 2000; 20: 7516-7526Crossref PubMed Scopus (136) Google Scholar, der Klei Kiel J.A.K.W. Cregg J.M. Veenhuis M. EMBO J. 17: PubMed Scopus Google Scholar). the target protein to which actually has a of which are involved in PTS1 matrix protein import, is actually to the receptor Pex5p during this observed in the yeast in human cell and in that the of of the peroxins proposed to function in receptor to steady-state levels of Pex5p A. Keller G.A. Subramani S. J. Cell Biol. PubMed Google Scholar, G. Gould S.J. J. Cell Biol. 1996; 135: PubMed Scopus Google Scholar, B. S. A. PubMed Scopus Google Scholar). This has actually been used to the in which a number of peroxins in matrix protein import C.S. Kalish J.E. Morrell J.C. McCaffery J.M. Gould S.J. Mol. Cell. Biol. 2000; 20: 7516-7526Crossref PubMed Scopus (136) Google Scholar). To this process also occurs in S. we the steady-state levels of Pex5p in various pex of this yeast we observed that in mutants of those PEX genes that are directly implicated in PTS1 import, steady-state Pex5p levels are enhanced with wild type Furthermore, we that the PTS1 receptor is ubiquitinated of the peroxins proposed to be required for Pex5p recycling Our data suggest the presence of a quality control mechanism at the Pex5p that the receptor be to the cytosol to of import be by the proteasome. and used in this are in and are of S. cerevisiae wild type R. A. J. A. Kunau W.H. Cell. 1991; Full Text PDF PubMed Scopus Google Scholar). mutants the S. T. J. 1996; PubMed Scopus Google Scholar). in which the of the by a by yeast with a to M. G. W. B. PubMed Scopus Google Scholar). The of used for the of these are cerevisiae used in this in a new and used for yeast have been described R. Veenhuis M. D. Kunau W.H. S. 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Biol. 2000; 20: 7516-7526Crossref PubMed Scopus (136) Google Scholar). we that ubiquitination of Pex5p in the and mutants on the of those peroxins that are required for PTS1 import. of in the of data suggested that the levels of Pex5p in wild type cells, with pex in PTS1 import, may actually from of a portion of the PTS1 receptor during its recycling to the cytosol. we Pex5p in a disturbed in the function of the which a of the the M. A. C. PubMed Scopus Google Scholar). a of Pex5p becomes degraded by the of proteasome function in the of ubiquitinated Pex5p that in the proteins of Pex5p are the with a deletion of these forms of Pex5p a still enhanced levels these Pex5p these suggest that the forms of Pex5p observed ubiquitinated of the PTS1 receptor We the of ubiquitinated forms of Pex5p in mutants of PEX genes that encode two of proteins and The of ubiquitinated Pex5p in a specific of S. cerevisiae pex mutants and its on other PEX genes is with the to certain peroxins in peroxisome biogenesis P.E. Lazarow P.B. Annu. Rev. Cell Dev. Biol. 2001; 17: 701-752Crossref PubMed Scopus (285) Google Scholar). Our data that these ubiquitinated forms of Pex5p are synthesized in mutants the peroxins and of which have been implicated in Pex5p of Pex5p observed in those pex mutants that of the peroxins to be involved in the of the peroxisomal membrane and in docking/translocation of PTS1 proteins Pex10p, Pex13p, Pex14p, and the of ubiquitinated Pex5p molecules in and to on the presence of these peroxins, which in the steps prior to receptor that these Pex5p molecules have actually most of the translocation at the peroxisomal membrane and have at a Pex5p is to the cytosol. at this of the receptor ubiquitination of Pex5p has we demonstrated that the ubiquitinated forms of Pex5p in the of and that these molecules are located at the peroxisomal membrane. data to be with that suggested a import of PTS1 matrix proteins in and C.S. Kalish J.E. Morrell J.C. McCaffery J.M. Gould S.J. Mol. Cell. Biol. 2000; 20: 7516-7526Crossref PubMed Scopus (136) Google Scholar), der Klei Kiel J.A.K.W. Cregg J.M. Veenhuis M. EMBO J. 17: PubMed Scopus Google Scholar), and B. S. A. PubMed Scopus Google the of of the peroxins in the in Pex5p a process that we to be on the ubiquitin-conjugating enzyme this ubiquitination is related to the function of which in a hitherto unknown is involved in Pex5p mutants on a for the observed Pex5p ubiquitination in peroxisome biogenesis. the ubiquitination of Pex5p is directly involved in recycling of the receptor to the cytosol, is the function of this protein We propose that this function is related to quality control of Pex5p at the peroxisomal membrane a peroxisomal import occurs a receptor cycle, Pex5p import, and in a highly import of PTS1 proteins into the peroxisome matrix. the recycling of Pex5p may function the receptor molecules be from the which be by ubiquitination of Pex5p by its via the proteasome. a process be highly enhanced recycling of Pex5p becomes in specific pex This is with the Pex5p levels in and cells, in human and cell and in A. A. 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Biol. 2000; 20: 7516-7526Crossref PubMed Scopus (136) Google Scholar), we have observed that S. cerevisiae mutants these peroxins have Pex5p levels wild type We this an that in S. cerevisiae wild type a number of Pex5p molecules may actually be This is by the that in a in proteasome ubiquitinated forms of Pex5p in a also deletion of the peroxisomal membrane protein of Pex5p in the This that also the observed at the peroxisomal membrane and ubiquitination of folded Pex5p molecules in the cytosol. Additionally, the forms of Pex5p we observed to forms of Pex5p containing on the of their on data to that these and Pex5p that have been to a single in the are of single at in the target only proteins with are degraded with by the proteasome V. C. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar, for see Ref. A. A. Annu. Rev. PubMed Scopus Google Scholar). in and a portion of Pex5p has that are to enable by the which in its at peroxisomal in these mutants a number of Pex5p molecules at the peroxisomal membrane may be to the proposed quality control may be the peroxisomal in only a in wild type cells, in these mutants the steady-state Pex5p levels are in mutants in PTS1 import. This suggests that also in these mutants a portion of Pex5p has been degraded via the and only those ubiquitinated receptor molecules that contain that are to be degraded by the are This is by the that of the of which the of and in an in the of ubiquitinated Pex5p molecules in and a be from a of the steady-state levels of Pex5p in S. and A. this cargo release into the lumen of the peroxisome, Pex5p has to be back to the cytosol. this the cell has to to the receptor to in a new of import, to via the proteasome. in certain Pex5p is to the cytosol, and only a in receptor recycling initiates a turnover of the receptor by the proteasome. these forms of Pex5p are that are degraded and other S. a these two and at a number of receptor molecules becomes ubiquitination of the receptor is certain in a the quality control mechanism also ubiquitinated forms of Pex5p, which are degraded by the their be that the described for the PTS1 receptor Pex5p is of the ubiquitination of S. cerevisiae which together with the receptor Pex7p is required for PTS2 import. Purdue and Lazarow P.E. Lazarow P.B. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google have demonstrated in wild type S. cerevisiae cells, becomes ubiquitinated in a and is being degraded by the proteasome. is also of a receptor cycle, and a quality control mechanism recycling and turnover of the is still to be from an of the that at the peroxisomal membrane during receptor this the of Erdmann H.W. Girzalsky W. Erdmann R. J. 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Kiel et al. (Wed,) studied this question.
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