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Mol Biol Cell. Jul 2003; 14(7): 2900–2907.
PMCID: PMC165685

Involvement of the Endoplasmic Reticulum in Peroxisome Formation

Gilmore Reid, Monitoring Editor

Abstract

The traditional view holds that peroxisomes are autonomous organelles multiplying by growth and division. More recently, new observations have challenged this concept. Herein, we present evidence supporting the involvement of the endoplasmic reticulum (ER) in peroxisome formation by electron microscopy, immunocytochemistry and three-dimensional image reconstruction of peroxisomes and associated compartments in mouse dendritic cells. We found the peroxisomal membrane protein Pex13p and the ATP-binding cassette transporter protein PMP70 present in specialized subdomains of the ER that were continuous with a peroxisomal reticulum from which mature peroxisomes arose. The matrix proteins catalase and thiolase were only detectable in the reticula and peroxisomes. Our results suggest the existence of a maturation pathway from the ER to peroxisomes and implicate the ER as a major source from which the peroxisomal membrane is derived.

INTRODUCTION

Peroxisomes belong to the repertoire of subcellular membrane-bounded compartments of the eukaryotic cell. Depending on species, they participate in cellular metabolism in various ways.

A consistent feature is the presence of H2O2-producing oxidases, such as enzymes degrading fatty acids, and catalase decomposing H2O2. Peroxisomes are bounded by a single membrane and morphologically range from rather inconspicuous small vesicles in some cells to elaborate tubular networks (reticula) in others (De Duve and Baudhuin, 1966 blue right-pointing triangle; Beevers, 1979 blue right-pointing triangle; van den Bosch et al., 1992 blue right-pointing triangle; Clayton et al., 1995 blue right-pointing triangle; Subramani et al., 2000 blue right-pointing triangle; Yamamoto and Fahimi, 1987 blue right-pointing triangle).

Mutations in genes coding for peroxisomal proteins cause a number of diseases extending from relatively mild ones in which the catalytic activity of an enzyme is affected to a number of different neuropathies in which a protein is affected that contributes to organelle maintenance (Lazarow and Moser, 1995 blue right-pointing triangle). Insight into this latter group of proteins was gained by studying peroxisome function and biogenesis in different yeasts and Chinese hamster ovary cells (Erdmann et al., 1989 blue right-pointing triangle; Ghaedi et al., 1999 blue right-pointing triangle). As a result, 25 PEX genes have been collected, 13 of which have orthologs in human and have been linked to disease (Gould and Valle, 2000 blue right-pointing triangle; Purdue and Lazarow, 2001 blue right-pointing triangle; Smith et al., 2002 blue right-pointing triangle).

Peroxisomal matrix and membrane proteins are synthesized on free polyribosomes and delivered to the cytosol. Here, they are picked up by soluble receptors on the basis of peroxisomal targeting signals (PTSs) and guided to the peroxisomal membrane for import into the organelle or insertion into the membrane. Most matrix proteins are recognized by Pex5p via a short C-terminal tripeptide (PTS1), whereas a limited number have an N-terminal sequence (PTS2) and are recognized by Pex7p. Pex3p and Pex19p have been implicated in recognition of targeting signals (mPTS) in integral membrane proteins and their insertion into the membrane (Jones et al., 2001 blue right-pointing triangle; Wang et al., 2001 blue right-pointing triangle). The PTS1 (Pex5p) and PTS2 (Pex7p) import routes converge on the peroxisomal membrane, where a number of proteins (Pex10p, Pex12p, Pex13p, Pex14p, and Pex17p) are involved in the membrane translocation step.

An important and still unresolved question is how peroxisomes acquire their phospholipids for membrane formation. The source of most phospholipid biosynthesis is the endoplasmic reticulum (ER), but how the newly synthesized phospholipids reach peroxisomes is not known. In early observations, peroxisomes were often seen in close association with the ER, which might allow unilateral transfer of phospholipids from the ER to peroxisomal membranes (Novikoff and Shin, 1964 blue right-pointing triangle). Even the idea of an ER origin of peroxisomes was entertained. However, with the authoritative review of Lazarow and Fujiki (1985 blue right-pointing triangle) compelling experimental evidence was presented on the basis of targeting of newly synthesized proteins to peroxisomes, which supported the notion that peroxisomes were autonomous organelles multiplying by growth and division.

In recent years, the possibility that the ER contributes to peroxisome formation has received renewed attention, particularly after observations that certain peroxisomal proteins or their modified derivatives were found in the ER (Titorenko and Rachubinski, 2001 blue right-pointing triangle; Faber et al., 2002 blue right-pointing triangle). In most cases, these observations were made in cells in which the expression level of such proteins was raised to support detection or which had been manipulated otherwise. Under these circumstances, mistargeting is possible and indeed examples of such mistargeting have recently been reported, suggesting that proper targeting of proteins in cells, particularly membrane proteins, is easily thrown off balance (Stroobants et al., 1999 blue right-pointing triangle; Borgese et al., 2001 blue right-pointing triangle). A convincing observation that still stands is that in Yarrowia lipolytica two peroxins (Pex2p and Pex16p) are N-glycosylated, suggesting that they passed through the ER en route to peroxisomes (Titorenko et al., 1997 blue right-pointing triangle). A critical summary of all the experiments relating to the ER–peroxisome connection was recently compiled by Purdue and Lazarow (2001 blue right-pointing triangle).

In the present article, we report new observations in unmanipulated mouse dendritic cells showing the ER to be involved in peroxisome formation particularly with respect to the delivery of the peroxisomal membrane. With these observations, we substantiate already more than 30-year-old work done by Phyllis and Alex Novikoff in which they showed intimate contacts and membrane continuities between ER and peroxisomes in intestinal cells by electron microscopy (Novikoff and Novikoff, 1972 blue right-pointing triangle).

MATERIALS AND METHODS

D1 cells were derived from immature splenic dendritic cells (DCs) from C57BL/6 mice and were cultured as described previously (Winzler et al., 1997 blue right-pointing triangle). In one experiment, human bone marrow-derived DCs were used for comparison. For immunocytochemistry, we used polyclonal antibodies against mouse I-chain luminal part (S22; kind gift of Dr. N. Koch, University of Bonn, Bonn, Germany), mouse langerine (Valladeau et al., 1999 blue right-pointing triangle), human protein disulfide isomerase (PDI; kindly provided by Dr I. Braakman, University of Utrecht, Utrecht, The Netherlands), rabbit anti-calreticulin was purchased from Affinity Bioreagents (Golden, CO), bovine catalase (Tager et al., 1985 blue right-pointing triangle), rat thiolase (Heikoop et al., 1990 blue right-pointing triangle), COPI (kindly provided by Dr. I. Majoul, University of Göttingen, Göttingen, Germany), Sec 13 (generously provided by Dr. W.J. Hong, Institute of Molecular and Cellular Biology, University of Singapore, Singapore), and rat PMP70 (Motley et al., 1994 blue right-pointing triangle). A mouse monoclonal was against PDI tail (Vaux et al., 1992 blue right-pointing triangle). Anti-Pex13p was raised against part of the SH3 domain (aa 275–454) of human Pex13p fused to the N terminus of dihydrofolate reductase. The antibody specifically cross-reacted with mouse Pex13p.

Immunocytochemistry

For immunocytochemistry, cells were washed by centrifugation in fetal calf serum-free medium and fixed in 2% paraformaldehyde and 0.2% glutaraldehyde. The cells were then processed as described previously (Liou et al., 1997 blue right-pointing triangle). Briefly, the fixed cells were washed in phosphate-buffered saline with 50 mM lysine at room temperature to quench free aldehydes, embedded in 10% gelatin, and cryosectioned. For immunoelectron microscopy, ultrathin cryosections were indirectly single or double immunolabeled with 5 nm of gold, or 10- and 15-nm gold particles, respectively (Geuze et al., 1981 blue right-pointing triangle; Liou et al., 1996 blue right-pointing triangle).

Quantitation of immunogold for Pex13p and PMP70 on the peroxisomal system, i.e., peroxisomes, peroxisomal reticula, and lamellae, was done in 20 random electron micrographs with a final magnification of 25,000×. In total, 304 gold particles were counted for Pex13 and 232 for PMP70. Relative membrane surface areas of the subcompartments of the peroxisomal system were determined by putting a transparent overlay with a squared lattice of 1 cm spaced lines on top of the same micrographs as used for gold counting. Labeling densities of Pex13p and PMP70 in the peroxisomal complex subdomains were calculated by determining the ratio's of the respective percentages of gold particles over the percentages of intersections between the lines and the various membranes involved.

Three-dimensional (3-D) Reconstruction

Approximately 150-nm thin cryosections were immunogold labeled for catalase with 10 nm of gold to visualize peroxisomal complexes. Selected fields in the sections were imaged at 17,280× in a Tecnai (S) LaB6 electron microscope (FEI/Philips, Eindhoven, The Netherlands) operating at 200 kV. For 3-D imaging of the sections by means of electron tomography (Koster et al., 1997 blue right-pointing triangle), the specimens were tilted at 10 intervals by using an ultra-high tilt specimen holder (model 670; Gatan, Pleasanton, CA) over a range of 1400 along two orthogonal axes (Mastronarde, 1997 blue right-pointing triangle). All images were collected with a 2048 × 2048 pixel cooled slow-scan charge-coupled device camera (TemCam F214; Tietz Video and Image Processing Systems, Gauting, Germany). At the magnification used, the images represent a specimen area of 1659 × 1659 nm. For the tilt series, images of 1024 × 1024 pixels with 1.6 nm/pixel were collected (binning 2). Automated acquisition of the tilt series was carried out using the recently developed precalibration approach (Ziese et al., 2002 blue right-pointing triangle). Postdata acquisition alignment of the tilt series, as well as the subsequent 3-D reconstructions (resolution-weighted back-projection) and modeling steps, were all carried out using the IMOD program (Kremer et al., 1996 blue right-pointing triangle) running on a Unix workstation (Octane2 dual-processor 2 × 400 MHz R12000 with 2.5 GB RAM; Silicon Graphics, Mountain View, CA). The 10-nm gold beads at the surface of the sections were used as landmarks for alignment of the tilt series. The shrinkage of cryosections was ~65% and we corrected for this in our model.

RESULTS

Dendritic cells exhibit a well-developed vacuolar system (Mellman and Steinman, 2001 blue right-pointing triangle) and numerous peroxisomes, providing a good starting point for a study on possible relationships between peroxisomes and other organelles. We choose for localizing critical marker proteins with immunoelectron microscopy, taking advantage of our recently developed cryosectioning technique, which allows for an excellent delineation of membranes (Liou et al., 1997 blue right-pointing triangle), together with electron tomography and 3-D reconstruction of peroxisomes and adjacent organelles. As markers, we studied the peroxisomal matrix proteins catalase and thiolase, which contain different targeting signals to enter the peroxisome (PTS1 and PTS2, respectively), and two peroxisomal integral membrane proteins: Pex13p, which is a component of the protein import complex (Elgersma et al., 1996 blue right-pointing triangle; Erdmann and Blobel, 1996 blue right-pointing triangle; Gould et al., 1996 blue right-pointing triangle; Stein et al., 2002 blue right-pointing triangle) and the ATP-binding cassette transporter PMP70 (Gartner et al., 1998 blue right-pointing triangle). As markers for the ER, we localized protein disulfide isomerase (PDI), invariant chain (Ii), calreticulin, and for the vesicular transport route, the coat proteins COPI and COPII.

Peroxisomes Are Closely Associated with Lamellar Structures Enriched in Pex13p and PMP70

The peroxisomes occurred in clusters throughout the cells. In these clusters different structures could be distinguished: 1) peroxisomes (P in the figures); 2) a reticulate peroxisomal network with globular extensions (Figure 1, B and C), and 3) tubular structures encircling the peroxisomal clusters with a special density and striping that we will subsequently call lamellae (Figures 1, A, B, and D; ;2A;2A; and and3).3). Characteristic features of the lamellae were the tightly opposed limiting membranes in thin sections and the internal structure seen as striping (best seen in Figure 1, A and C). The lamellae resembled the so-called Birbeck granules in Langerhans cells. However, Birbeck granules are thicker, present a different striping pattern, and are associated with the plasma membrane and endosomes. In addition, Birbecks strongly labeled with an antibody against the Birbeck marker protein langerine, whereas the peroxisome-associated rigid lamellae did not (our unpublished data).

Figure 1.
Clusters of peroxisomes are associated with lamellae and peroxisomal reticula. (A) Survey of an area with lamellae and peroxisomes (P). Pex13p labeling is predominantly associated with the lamellae and is almost absent from the peroxisomes. Note that ...
Figure 2.
Adjacent to peroxisomes the ER shows lamellar subdomains. A.Peroxisome immunolabeled for catalase is surrounded by a lamella that shows membrane continuity with the ER (arrowhead). At the transition, the ER lumen is narrowed. See also in B. B. Like ...
Figure 3.
ER that is continuous with lamellae contains ER markers. (A and B) ER cisternae with membrane connections to lamellae (arrowheads) and that are labeled for Ii and calreticulin, respectively. (C) Pex13p-positive lamella continuous with ER labeled for ...

Various marker proteins showed different distributions with respect to these structures. The peroxisomes and reticula, but not the lamellae were positive for catalase and thiolase (Figures (Figures1C; 1C; 2, A and B). The rigid lamellae, on the other hand, contained abundant Pex13p (Figure 1, A, C, and D) and PMP70 (Figure 1B). Both membrane proteins were also present on the limiting membrane of peroxisomes and peroxisomal reticulum, albeit with different densities. A quantitative evaluation of the gold labeling patterns showed that of all Pex13p present in the peroxisomal system, 64% was present in the lamellae, 27% in the reticula, and only 9% in the peroxisomes. For PMP70, these figures were 12, 62, and 26%, respectively. Thus, by far the majority of Pex13p was located outside the typical globular peroxisomes, in particular in the lamellae. For PMP70, this distribution was reverse, i.e., shifted toward the reticula and peroxisomes (Table 1). When we related the gold labeling to the membrane surface areas in these structures to reveal labeling densities (see MATERIALS AND METHODS), the highest Pex13p density occurred in the lamellae and that of PMP70 in the peroxisomes. For both proteins, the peroxisomal reticula took an intermediate position (Table 1).

Table 1.
Distribution of Pex13p and PMP70 in peroxisomal clusters

Peroxisome-associated Lamellae Represent a Subdomain of the ER

Interestingly, lamellae were also observed as protrusions from the ER. In all figures shown, these membrane continuities between the rough ER cisternae and lamellae have been marked with arrows (Figures 1, A and D; 2, A–C; and and3).3). Considering the importance of this observation, we have studied this aspect in further detail.

The lamellae lacked ribosomes and any visible cytoplasmic coat (best seen in Figures Figures1A, 1A, ,2A,2A, and and3A).3A). That it was the ER with which the lamellae were continuous was further demonstrated by labeling for the ER markers PDI (Figure 2C) and calreticulin (Figure 3, B and C). As a powerful antigen-presenting cell type, dendritic cells contain large amounts of the major histocompatability complex class II chaperone Ii, especially in the ER. With all three ER markers, we demonstrate now that the lamellae are directly connected to ER cisternae. The absence of ribosomes from the lamellae and their continuity with the ER was reminiscent of the smooth transitional elements of the ER facing the cis-Golgi, which represent the COP II-coated exit sites for newly synthesized secretory, lysosomal, and membrane proteins for transport from the ER to the Golgi complex. However, the lamellae were negative for sec 13, a component of COP II. COP I, thought to be involved in retrograde transport from the Golgi to downstream elements of the secretory pathway, was also absent from the lamellae. Both COPs were present in the Golgi areas in the same sections (our unpublished data). Our observations show that the lamellae are subdomains of the ER, and the position of the marker proteins in the various structures suggests that the lamellae are engaged in peroxisome formation.

3-D Analysis Reveals an Anastomosing Membrane System Interconnecting ER and Peroxisomes

For a more comprehensive view on the intricate membranous relationships between the above-mentioned peroxisomal subcompartments, we made 3-D reconstructions of dual-axis tilt series of entire peroxisomal clusters. Figure 4A shows a peroxisomal cluster with lamellae, reticulum, and peroxisomes labeled for catalase. Of the squared area several tomographic slices (5 nm in thickness) were obtained as depicted in B–I. The membranes were manually traced as illustrated in F to generate the 3-D model shown in J. The lamellae seemed to be sheets that formed a complex network. The 3-D reconstructions confirmed their connection with the ER and the peroxisomal reticulae. Together, our data suggest a model for peroxisomal biogenesis as depicted in Figure 4K.

Figure 4.
A 3-D reconstruction of the spatial relationships between lamellae and peroxisomal reticulum. (A) Electron micrograph of a 150-nm-thick cryosection labeled for catalase with 10 nm of gold, showing lamellae (L) and reticula (R). (B–I) Several ...

DISCUSSION

In this study, we present evidence in favor of a contribution of the ER to the formation of peroxisomes in an unmanipulated cell. The mouse dendritic cell line D1 can be propagated in vitro in the presence of granulocyte-macrophage colony-stimulating factor and fibroblast-derived growth factors (Lutz et al., 1996 blue right-pointing triangle). When stocks of D1 cells were taken and put into culture for various periods, we observed special lamellar structures that were connected to the ER (“specialized ER”) and that contained the peroxisomal proteins Pex13p and PMP70. Similar structures were found in bone marrow-derived human dendritic cells. The reason for the abundance of the lamellar structures in dendritic cells is unknown. However, it is of interest to note that dendritic cells were reported to contain peroxisome proliferator-activated receptor (PPAR)γ, a member of the PPARs, which upon activation stimulate among others the formation of new peroxisomes (Gosset et al., 2001 blue right-pointing triangle). It is conceivable that the special growth medium required for the in vitro cultivation of dendritic cells contains ligands that put PPARγ into action. Pex13p, an integral membrane protein, which is involved in import of matrix proteins into peroxisomes, was abundantly present in the lamellae. The lamellae were often seen as extensions of the ER. The identity of the ER was confirmed by the localization of three different marker proteins: PDI, calreticulin, and Ii. This specialized ER was morphologically different from the ER itself. It lacked associated ribosomes and its narrow lumen showed a characteristic striping. The lamellar extensions of the ER contained only very small amounts of the luminal ER markers PDI, calreticulin, and Ii. We concluded that the lamellar extensions of the ER are specialized subcompartments of the ER. Our 3-D reconstructions showed that free lamellae that were not connected to the ER were continuous with the peroxisomal reticulum, the precursor compartment of the globular peroxisomes (Yamamoto and Fahimi, 1987 blue right-pointing triangle; Schrader et al., 2000 blue right-pointing triangle). Quantification of immunogold indicated the existence of a protein gradient with respect to these structures, with Pex13p highest in the lamellar ER domains and free lamellae, the ATP-binding cassette transporter protein PMP70 highest in the reticula and peroxisomes, and thiolase and catalase exclusively present in wide portions of the reticula and globular peroxisomes. Considering the fact that components of the protein import machinery must be assembled first, before the import of PTS1 or PTS2 containing matrix proteins can start, the marker proteins combined with their subcellular locations suggest the existence of a maturation pathway. The observations favor a model in which certain integral peroxisomal membrane proteins are recruited to the specialized ER subdomains, or are sorted toward these domains from other regions of the ER to form the lamellar ER extensions. Once formed, additional integral membrane proteins are recruited for building up the protein-import machinery. With the start of matrix protein import, the formation of reticula and globular peroxisomes is concluded. How Pex13p finds its position in the specialized ER is difficult to answer at the moment. Studies in yeast argue that peroxisomes can still be formed in the absence of a functional ER protein import complex (South et al., 2001 blue right-pointing triangle). However, the mandatory application of mutants (ts sec61 and Δssh1), the use of GFP-PTS1 as a late read out for peroxisome formation and the presence of residual fluorescent, unidentified punctate structures may still leave room for alternative explanations. It is likely that at a certain stage cytosolic factors are involved in severing the specialized ER compartment from its donor compartment. In the past, much effort has been invested in attempts to find clues for vesicular trafficking from ER to peroxisomes that possibly involved components of the well-characterized COPI- and COPII-dependent processes in membrane traffic (South et al., 2000 blue right-pointing triangle; Voorn-Brouwer et al., 2001 blue right-pointing triangle). Thus far, these attempts have all been negative. Also in our present study, we were unable to detect COP coats on the lamellar extensions of the ER, although in the same preparations COPI and COPII were found in the Golgi region. Our results suggest an explanation for this, because they indicate that large pieces of ER membrane are selected for peroxisome formation, which obviates the need for proteins required for small vesicle formation. More likely candidates for this severing process, therefore, might be components involved in organelle fission events such as the dynamins and/or SNARE proteins. This is borne out by our recent observations in Saccharomyces cerevisiae that Vps1p, a dynamin-like protein involved in routing of vesicles from Golgi to vacuole, is also responsible for keeping a constant number of peroxisomes per cell. The involvement of Myo2p in peroxisome partitioning, a motor protein that is also responsible for the delivery of the vacuole to the emerging bud additionally argues in favor of shared features between peroxisomes and the vacuole compartment (Hoepfner et al., 2001 blue right-pointing triangle). Together, our results challenge the concept that peroxisomes are autonomous organelles and rather support a semiautonomous character. To form the preperoxisome, the organelles are dependent on a priming event that occurs in the ER. The ER provides the membrane and one or a few integral membrane proteins. From then on further maturation takes place in an autonomous manner.

Our results are based on morphological observations. It will be important to confirm these data and to further characterize the implications of this new concept by biochemical means. Considering the fact that the lamellar intermediate structures represent a minority within the variety of membranous compartments of a cell, it will be a difficult task to enrich them, particularly in view of the special growth conditions required for cultivation and the inherent biological complexity of dendritic cells. We hope that our observations provide a stimulus to readdress the controversial issue of ER involvement in peroxisome formation from a new perspective using new genetic screens and biochemical approaches.

Acknowledgments

We are highly indebted to Rene Scriwanek and Marc van Peski for printing the micrographs, Ulrike Ziese for helping with the tomography software, Misjaël N. Lebbink for combining the two tomograms in the reconstruction, Dr. Paola Ricciardi-Castagnoli (Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy) for providing the D1 cells, and Tineke Voorn-Brouwer for preparing the anti-Pex13p antibodies. The research of A.J.K. has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences (KNAW). A.K.S. was supported by the Medical Science department of the Netherlands Foundation for Scientific Research (NWO-MW)

Notes

Abbreviations used: COP, coatomer protein; DC, dendritic cell; ER, endoplasmic reticulum; Ii, invariant chain; PDI, protein disulfide isomerase; Pex, peroxin; PEX, gene coding for peroxin; PMP, peroxisomal membrane protein; PTS, peroxisomal targeting signal.

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