Reactome | Peroxisomal protein import

Peroxisomal protein import

Stable Identifier

R-HSA-9033241

DOI

10.3180/R-HSA-9033241.1

Type

Pathway

Species

Homo sapiens

Compartment

cytosol, peroxisomal matrix, peroxisomal membrane

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Click the image above or here to open this pathway in the Pathway Browser

Peroxisomes are small cellular organelles that are bounded by a single membrane and contain variable compositions of proteins depending on cell type. Peroxisomes function in oxidation of fatty acids, detoxification of glyoxylate, and synthesis of plasmalogens, glycerophospholipids containing an alcohol with a vinyl-ether bond (reviewed in Lohdi and Semenkovich 2014). All of the approximately 46 proteins contained in peroxisomal matrix are imported from the cytosol by a unique mechanism that does not require the imported proteins to be unfolded as they cross the membrane (Walton et al. 1995, reviewed in Ma et al. 2011, Fujiki et al. 2014, Baker et al. 2016, Dias et al 2016, Emmanoulidis et al. 2016, Erdmann 2016, Francisco et al. 2017). The incompletely characterized process appears to involve the transport of the proteins through a variably sized pore in the membrane comprising at least PEX5 and PEX14 (inferred from the yeast homologs in Meinecke et al. 2010, the yeast pore is reviewed in Meinecke et al. 2016). Oligomeric proteins are also observed to cross the peroxisomal membrane (Otera and Fujiki 2012) but their transport appears to be less efficient than monomeric proteins (Freitas et al. 2011, inferred from mouse homologs in Freitas et al. 2015, reviewed in Dias et al. 2016).
In the cytosol, receptor proteins, PEX5 and PEX7, bind to specific sequence motifs in cargo proteins (Dodt et al. 1995, Wiemer et al. 1995, Braverman et al. 1997). The long and short isoforms of PEX5 (PEX5L and PEX5S) bind peroxisome targeting sequence 1 (PTS1, originally identified in firefly luciferase by Gould et al. 1989) found on most peroxisomal matrix proteins; PEX7 binds PTS2 (originally identified in rat 3-ketoacyl-CoA thiolase by Swinkels et al. 1991) found on 3 imported proteins thus far in humans. The long isoform of PEX5, PEX5L, then binds the PEX7:cargo protein complex (Braverman et al. 1998, Otera et al. 2000). PEX5S,L bound to a cargo protein or PEX5L bound to PEX7:cargo protein then interacts with a complex comprising PEX13, PEX14, PEX2, PEX10, and PEX12 at the peroxisomal membrane (Gould et al. 1996, Fransen et al. 1998, inferred from rat homologs in Reguenga et al. 2001).
The ensuing step in which the cargo protein is translocated across the membrane is not completely understood. During translocation, PEX5 and PEX7 become inserted into the membrane (Wiemer et al. 1995, Dodt et al. 1995, Oliveira et al. 2003) and expose a portion of their polypeptide chains to the organellar matrix (Rodrigues et al. 2015). One current model envisages PEX5 as a plunger that inserts into a transmembrane barrel formed by PEX14, PEX13, PEX2, PEX10, and PEX12 (the Docking-Translocation Module) (Francisco et al. 2017).
After delivering cargo to the matrix, PEX5 and PEX7 are recycled back to the cytosol by a process requiring mono-ubiquitination of PEX5 and ATP hydrolysis (Imanaka et al. 1987, Thoms and Erdmann 2006, Carvalho et al. 2007). PEX7 is not ubiquitinated but its recycling requires PEX5 mono-ubiquitination. A subcomplex of the Docking-Translocation Module comprising the RING-finger proteins PEX2, PEX10, and PEX12 conjugates a single ubiquitin to a cysteine residue of PEX5 (Carvalho et al. 2007, reviewed in Platta et al. 2016). The mono-ubiquitinated PEX5 and associated PEX7 are then extracted by the exportomer complex consisting of PEX1, PEX6, PEX26, and ZFAND6 (inferred from rat homologs in Miyata et al. 2012). PEX1 and PEX6 are members of the ATPases Associated with diverse cellular Activities (AAA) family, a group of proteins that use the energy of ATP hydrolysis to remodel molecular complexes. PEX1 and PEX6 form a hetero-hexameric ring, best described as a trimer of PEX1/PEX6 dimers (inferred from yeast in Platta et al. 2005, yeast homologs reviewed in Schwerter et al. 2017). Data on the yeast PEX1:PEX6 complex suggest that these ATPases use a substrate-threading mechanism to disrupt protein-protein interactions (Gardner et al. 2018). PEX7 is also then returned to the cytosol (Rodrigues et al. 2014). Once in the cytosol, ubiquitinated PEX5 is enzymatically deubiquitinated by USP9X and may also be non-enzymatically deubiquitinated by nucleophilic attack of the thioester bond between ubiquitin and the cysteine residue of PEX5 by small metabolites such as glutathione (Grou et al. 2012).
Defects in peroxisomal import cause human diseases: Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata types 1 and 5 (Barøy et al. 2015, reviewed in Nagotu et al. 2012, Braverman et al. 2013, Wanders 2014, Fujiki 2016, Waterham et al. 2016).

Literature References

PubMed ID	Title	Journal	Year
9090381	Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata Braverman, N, Steel, G, Obie, C, Moser, A, Moser, H, Gould, SJ, Valle, D	Nat. Genet.	1997
27977397	ATP-driven processes of peroxisomal matrix protein import Schwerter, DP, Grimm, I, Platta, HW, Erdmann, R	Biol. Chem.	2017
23798008	Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives Braverman, NE, D'Agostino, MD, Maclean, GE	Dev Disabil Res Rev	2013
25854684	The peroxisomal protein import machinery displays a preference for monomeric substrates Freitas, MO, Francisco, T, Rodrigues, TA, Lismont, C, Domingues, P, Pinto, MP, Grou, CP, Fransen, M, Azevedo, JE	Open Biol	2015
21976670	PEX5 protein binds monomeric catalase blocking its tetramerization and releases it upon binding the N-terminal domain of PEX14 Freitas, MO, Francisco, T, Rodrigues, TA, Alencastre, IS, Pinto, MP, Grou, CP, Carvalho, AF, Fransen, M, Sá-Miranda, C, Azevedo, JE	J. Biol. Chem.	2011
22617146	Molecular basis of peroxisomal biogenesis disorders caused by defects in peroxisomal matrix protein import Nagotu, S, Kalel, VC, Erdmann, R, Platta, HW	Biochim. Biophys. Acta	2012
26138649	Revisiting the intraperoxisomal pathway of mammalian PEX7 Rodrigues, TA, Grou, CP, Azevedo, JE	Sci Rep	2015
25177298	Peroxisome biogenesis in mammalian cells Fujiki, Y, Okumoto, K, Mukai, S, Honsho, M, Tamura, S	Front Physiol	2014
26450166	Structural biology of the import pathways of peroxisomal matrix proteins Emmanouilidis, L, Gopalswamy, M, Passon, DM, Wilmanns, M, Sattler, M	Biochim. Biophys. Acta	2016
17028012	Peroxisomal matrix protein receptor ubiquitination and recycling Thoms, S, Erdmann, R	Biochim. Biophys. Acta	2006
16007078	Functional role of the AAA peroxins in dislocation of the cycling PTS1 receptor back to the cytosol Platta, HW, Grunau, S, Rosenkranz, K, Girzalsky, W, Erdmann, R	Nat. Cell Biol.	2005
26220973	A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform Barøy, T, Koster, J, Strømme, P, Ebberink, MS, Misceo, D, Ferdinandusse, S, Holmgren, A, Hughes, T, Merckoll, E, Westvik, J, Woldseth, B, Walter, J, Wood, N, Tvedt, B, Stadskleiv, K, Wanders, RJA, Waterham, HR, Frengen, E	Hum. Mol. Genet.	2015
11397814	Characterization of the mammalian peroxisomal import machinery: Pex2p, Pex5p, Pex12p, and Pex14p are subunits of the same protein assembly Reguenga, C, Oliveira, ME, Gouveia, AM, Sá-Miranda, C, Azevedo, JE	J. Biol. Chem.	2001
20154681	The peroxisomal importomer constitutes a large and highly dynamic pore Meinecke, M, Cizmowski, C, Schliebs, W, Krüger, V, Beck, S, Wagner, R, Erdmann, R	Nat. Cell Biol.	2010
26497277	Peroxisomal protein import pores Meinecke, M, Bartsch, P, Wagner, R	Biochim. Biophys. Acta	2016
17726030	Ubiquitination of mammalian Pex5p, the peroxisomal import receptor Carvalho, AF, Pinto, MP, Grou, CP, Alencastre, IS, Fransen, M, Sá-Miranda, C, Azevedo, JE	J. Biol. Chem.	2007
26408939	The first minutes in the life of a peroxisomal matrix protein Dias, AF, Francisco, T, Rodrigues, TA, Grou, CP, Azevedo, JE	Biochim. Biophys. Acta	2016
28787099	Protein transport into peroxisomes: Knowns and unknowns Francisco, T, Rodrigues, TA, Dias, AF, Barros-Barbosa, A, Bicho, D, Azevedo, JE	Bioessays	2017
24508507	Peroxisomes: a nexus for lipid metabolism and cellular signaling Lodhi, IJ, Semenkovich, CF	Cell Metab.	2014
1680677	A novel, cleavable peroxisomal targeting signal at the amino-terminus of the rat 3-ketoacyl-CoA thiolase Swinkels, BW, Gould, SJ, Bodnar, AG, Rachubinski, RA, Subramani, S	EMBO J.	1991
9668159	An isoform of pex5p, the human PTS1 receptor, is required for the import of PTS2 proteins into peroxisomes Braverman, N, Dodt, G, Gould, SJ, Valle, D	Hum. Mol. Genet.	1998
27941306	Peroxisome biogenesis and human peroxisome-deficiency disorders Fujiki, Y	Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci.	2016
26851075	Assembly, maintenance and dynamics of peroxisomes Erdmann, R	Biochim. Biophys. Acta	2016
26367801	Regulation of peroxisomal matrix protein import by ubiquitination Platta, HW, Brinkmeier, R, Reidick, C, Galiani, S, Clausen, MP, Eggeling, C	Biochim. Biophys. Acta	2016
10767286	The mammalian peroxin Pex5pL, the longer isoform of the mobile peroxisome targeting signal (PTS) type 1 transporter, translocates the Pex7p.PTS2 protein complex into peroxisomes via its initial docking site, Pex14p Otera, H, Harano, T, Honsho, M, Ghaedi, K, Mukai, S, Tanaka, A, Kawai, A, Shimizu, N, Fujiki, Y	J. Biol. Chem.	2000
7719337	Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders Dodt, G, Braverman, N, Wong, C, Moser, A, Moser, HW, Watkins, P, Valle, D, Gould, SJ	Nat. Genet.	1995
26611709	Human disorders of peroxisome metabolism and biogenesis Waterham, HR, Ferdinandusse, S, Wanders, RJA	Biochim. Biophys. Acta	2016
22371489	Identification of ubiquitin-specific protease 9X (USP9X) as a deubiquitinase acting on ubiquitin-peroxin 5 (PEX5) thioester conjugate Grou, CP, Francisco, T, Rodrigues, TA, Freitas, MO, Pinto, MP, Carvalho, AF, Domingues, P, Wood, SA, Rodríguez-Borges, JE, Sá-Miranda, C, Fransen, M, Azevedo, JE	J. Biol. Chem.	2012
21464226	Peroxisome assembly: matrix and membrane protein biogenesis Ma, C, Agrawal, G, Subramani, S	J. Cell Biol.	2011
12885776	The energetics of Pex5p-mediated peroxisomal protein import Oliveira, ME, Gouveia, AM, Pinto, RA, Sá-Miranda, C, Azevedo, JE	J. Biol. Chem.	2003
2654139	A conserved tripeptide sorts proteins to peroxisomes Gould, SJ, Keller, GA, Hosken, N, Wilkinson, J, Subramani, S	J. Cell Biol.	1989
21980954	AWP1/ZFAND6 functions in Pex5 export by interacting with cys-monoubiquitinated Pex5 and Pex6 AAA ATPase Miyata, N, Okumoto, K, Mukai, S, Noguchi, M, Fujiki, Y	Traffic	2012
29321502	The peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading Gardner, BM, Castanzo, DT, Chowdhury, S, Stjepanovic, G, Stefely, MS, Hurley, JH, Lander, GC, Martin, A	Nat Commun	2018
9653144	Identification of a human PTS1 receptor docking protein directly required for peroxisomal protein import Fransen, M, Terlecky, SR, Subramani, S	Proc. Natl. Acad. Sci. U.S.A.	1998
8858165	Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic PTs1 receptor Gould, SJ, Kalish, JE, Morrell, JC, Bjorkman, J, Urquhart, AJ, Crane, DI	J. Cell Biol.	1996
3693402	Translocation of acyl-CoA oxidase into peroxisomes requires ATP hydrolysis but not a membrane potential Imanaka, T, Small, GM, Lazarow, PB	J. Cell Biol.	1987
7579687	Import of stably folded proteins into peroxisomes Walton, PA, Hill, PE, Subramani, S	Mol. Biol. Cell	1995
24865970	A PEX7-centered perspective on the peroxisomal targeting signal type 2-mediated protein import pathway Rodrigues, TA, Alencastre, IS, Francisco, T, Brites, P, Fransen, M, Grou, CP, Azevedo, JE	Mol. Cell. Biol.	2014
22747494	Pex5p imports folded tetrameric catalase by interaction with Pex13p Otera, H, Fujiki, Y	Traffic	2012
27284042	Peroxisome protein import: a complex journey Baker, A, Lanyon-Hogg, T, Warriner, SL	Biochem. Soc. Trans.	2016