MINIREVIEW:
Complex, Two-way Traffic of Molecules
Across the Membrane of the Endoplasmic
Reticulum
Tadashi Suzuki, Qi Yan and William J.
Lennarz
J. Biol. Chem. 1998, 273:10083-10086.
doi: 10.1074/jbc.273.17.10083
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THE JOURNAL OF BIOLOGICAL CHEMISTRY
Vol. 273, No. 17, Issue of April 24, pp. 10083–10086, 1998
© 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
Printed in U.S.A.
Minireview
Complex, Two-way Traffic of
Molecules Across the Membrane
of the Endoplasmic Reticulum*
Tadashi Suzuki‡, Qi Yan, and William J. Lennarz§
From the Department of Biochemistry and Cell Biology
and the Institute for Cell and Developmental Biology,
State University of New York,
Stony Brook, New York 11794
Protein Import and N-Glycosylation of
Proteins in the ER
Protein import from the cytosol to the lumen of the ER, the
first step in the biosynthesis of luminal and/or secretory proteins, occurs by either a co- or post-translational process (1–3).
In both cases, proteins are known to cross the membrane by a
protein-conducting channel, the translocon, in which the
Sec61p trimeric complex is believed to play a central role in
mammalian cells. During the co-translocational insertion of
proteins into the ER the enzyme oligosaccharyltransferase
(OST) transfers an oligosaccharyl moiety, in most cases
GlcNAc2Man9Glc3, from the dolichol intermediate to Asn residues located within the sequence -Asn-X-Ser/Thr- to form Nlinked glycans on the nascent polypeptide chain. The enzyme
complex has been characterized both in mammals and yeast;
four subunits have been identified in the mammalian system,
and so far eight subunits have been found in Saccharomyces
cerevisiae (4). The spatial relationship of this enzyme with
respect to the translocon remains to be determined. Also still
unknown is the process whereby the oligosaccharide lipid, DolPP-GlcNAc2Man9Glc3, that serves as donor of its oligosaccha* This minireview will be reprinted in the 1998 Minireview Compendium, which will be available in December, 1998.
‡ Recipient of an Overseas Research Fellowship from the Mochida
Memorial Foundation for Medical and Pharmaceutical Research.
§ Recipient of National Institutes of Health Grant GM33184.
1
The abbreviations used are: ER, endoplasmic reticulum; OST, oligosaccharyltransferase; Dol, dolichol; PNGase, peptide:N-glycanase;
TAP, transporter associated with antigen processing; ENGase, endob-N-acetylglucosaminidase.
This paper is available on line at http://www.jbc.org
Peptides Glycosylated in the ER Are Exported
to the Cytosol
Following the demonstration that unfolded proteins and simple tripeptides containing -Asn-X-Thr/Ser- sequences could be
glycosylated in vitro using microsomes (12, 13), the fate of such
glycopeptides when formed in vivo was studied with the view
that they would serve as so-called markers for the secretory
pathway. Although it was reported that in HepG2 cells newly
formed glycopeptides could be secreted and thereby serve as
markers for non-selective, “bulk flow” through the ER (14),
subsequent studies in other biological systems have not supported this idea. For example, studies using frog oocytes injected with glycosylatable peptides showed that the glycopeptides formed were not secreted but slowly degraded in a process
inhibited by chloroquine; this observation suggested that lysosomes could be involved (15). Furthermore, in vitro studies in
S. cerevisiae also showed that in this system glycopeptides were
not exported like secretory proteins and that their exit from the
ER (presumably to the cytosol) involved ATP and cytosol (16).
There now is growing evidence that flow through the ER is by
no means non-selective, and there is a mechanism that functions to concentrate cargo proteins during exit from the ER
(17).
In contrast to the results using the yeast system, an initial
attempt to detect glycopeptides exported from the ER to the
cytosol using a mammalian system was not successful (18).
This lack of success may have been due to the presence of a
recently described peptide:N-glycanase (PNGase) activity in
the soluble (cytosol) fractions of all mammalian cell lines and
tissues studied (19, 20). The action of this enzyme in the cytosol
(21) would cleave the glycopeptides at the bond linking the
10083
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It has been known for many years that the endoplasmic
reticulum (ER)1 is the site of assembly of polypeptide chains
destined either for secretion or routing into various subcellular
compartments. The N-glycosylation of these proteins, as well as
their maturation assisted by certain resident luminal proteins,
also occurs in the ER. Although many features of the import
processes involved in synthesis of these glycoproteins have
been elucidated, what is now becoming apparent is that the ER
is not only involved in translocation and import, but it also
functions in novel processes that mediate the export of a diversity of molecules, including unfolded or misfolded glycoproteins, glycopeptides, and oligosaccharides into the cytosol.
Thus, it is clear that two-way traffic occurs, involving not only
movement of molecules from the cytosol into the lumen of the
ER but also out of the lumen into the cytosol. In this review the
components involved in import of proteins into the ER, which
have been reviewed elsewhere (1–3), are considered only in so
far as they are implicated in the retrograde process, namely
export out of the ER to the cytosol.
ride chain in the OST-catalyzed reaction is assembled. This
assembly process is believed to involve translocation within the
ER membrane, i.e. “flip-flop” of some of the intermediates leading to formation of Dol-PP-GlcNAc2Man9Glc3. The currently
accepted model is that assembly of the lipid-linked oligosaccharide occurs at the membrane of the ER in a stepwise manner
(5– 8), and three molecules are implicated in translocation from
the cytosol to the lumen, namely Dol-PP-GlcNAc2Man5, Dol-PMan, and Dol-P-Glc. However, so far putative “flippases” to
facilitate this energetically unfavorable process have not been
identified. In addition, there is no information on the topological orientation of Dol-P in the lipid bilayer of the ER.
Although much less is known about post-translational insertion of proteins into the ER, most of what is known has been
elucidated in S. cerevisiae. In the post-translational pathway,
the targeting of polypeptides is independent of ribosomes or the
signal recognition particles. Instead, ER membrane proteins,
namely the Sec62p and Sec63p subcomplex, are believed to be
important. In addition, a heat shock protein (hsp70) with
ATPase activity is thought to function in maintaining the
polypeptide chain in a loosely folded state to facilitate the
translocation (9). From in vivo and in vitro experiments, it has
been concluded that an ER-resident protein, BiP, also has an
important role in this process. In one model, it is speculated
that BiP binds to a portion of the polypeptide chain as it
protrudes through the Sec61p complex, thereby preventing the
peptide chain from sliding back through the membrane of the
ER (10). In a second model, BiP is thought to actively pull the
polypeptide across the ER membrane (11).
10084
Minireview: Two-way Traffic Across the ER Membrane
FIG. 1. Traffic in and out of the ER.
Gn2-OS represents for simplicity oligosaccharides with N-acetylglucosamine at the
reducing terminus whose complete structure is not defined. Solid lines represent
processes that have already been described, whereas broken lines represent
reactions that either are controversial or
undocumented. The subcellular site for
the deglycosylation by PNGase is still unclear, although the occurrence of this enzyme in both cytosol and in the ER has
been reported (see the text).
Similar Findings Indicate That Misfolded Proteins
Also Leave the ER and Enter the Cytosol
Recent evidence indicates that the ER has “quality control”
machinery (25) that differentiates between unfolded or misfolded proteins and correctly folded proteins so that the latter
move from the ER to the Golgi complex. In this system, proteins
that fail to correctly fold and/or oligomerize are retained in the
ER and interact with a number of chaperones that serve to
facilitate their acquisition of the correct conformation before
they exit the ER by means of the secretory path. However,
proteins that are misfolded (which could be deleterious to cells)
are known to be degraded by a mechanism formerly called “ER
degradation” (26). Until recently, the nature of this degradation process has remained unclear, because earlier attempts to
identify the responsible proteolytic activities in the ER failed.
Now it is evident that the site for the degradation is, in fact, the
cytosol rather than the ER (27–30) and that membrane or
secretory proteins can be translocated from the ER into the
cytosol, where they are degraded by proteasomes (Fig. 1). In
some cases, it has been reported that the glycoproteins are
deglycosylated by the action of PNGase prior to proteolytic
degradation (31–35), although the precise subcellular location
of this deglycosylation reaction remains unclear (see below).
Furthermore, recent studies suggest that the Sec61p complex
also participates in the retrograde translocation of proteins
from the ER to cytosol (36 –38). This mechanism to route malformed proteins from the ER to cytosol was also shown to exist
in S. cerevisiae (37– 46), suggesting that this quality control
system may occur widely in nature. It should be noted that the
retrograde movement of polypeptides across the ER, possibly
by the action of a translocon, has been previously proposed (47,
48). This route for movement of proteins from the ER to cytosol
was suspected based on the finding that toxic proteins that
enter the ER kill the cell by inactivating protein synthesis in
the cytosol (49). Very recently this idea was confirmed by
showing that a mutant ricin A-chain was transported from the
ER to the cytosol in this retrograde manner (50). These findings
suggest that the toxin molecules are routed to the cytosol by a
preexisting transport mechanism that can also be used to export unfolded proteins.
In S. cerevisiae, considerable progress has been made in
identifying ER components in addition to the Sec61p complex
that are involved in this export and degradation process.
Among these is Ubc6p, which is a ubiquitin-conjugating enzyme that catalyzes the covalent attachment of ubiquitin to
specific proteolytic substrates (41). Recently, Cue1p, an ER
membrane protein, has been shown to recruit soluble Ubc7p,
another ubiquitin-conjugating enzyme to the ER surface. The
action of these conjugation enzymes appears to be a prerequisite for retrograde transport out of the ER, suggesting a coupling of export and degradation (45). Another ER protein,
Der1p, has been described (40); although its function is unknown, it is postulated to be necessary for export to the cytosol
of soluble luminal proteins that are then degraded (26). The
protein encoded by the HRD1/DER3 gene, originally believed to
be involved in regulating the level hydroxymethylglutaryl-CoA
reductase in the ER, seems to play an even broader role in
degradation of both membrane and luminal proteins (44, 46).
Hrd3p is also believed to be an ER membrane protein involved
in the transport of hydroxymethylglutaryl-CoA, although its
precise function is not clear (44). With respect to chaperones in
the lumen of ER of yeast, thus far, Cne1p (calnexin) (39) and
Kar2p (BiP) (37) have been suggested to be involved in the
export process. There also is preliminary evidence that Pdi1p
(protein disulfide isomerase) is involved in the export of malfolded proteins.2 In contrast to yeast, in higher eukaryotes
little is known about components of the ER other than in
cytomegalovirus-infected cells, in which two viral gene products, US11 and US2 proteins, have been shown to bind to newly
synthesized class I heavy chains and thereby facilitate their
rapid routing back to the cytosol (31, 36). Given the recent
identification of multiple components of the export and degradation machinery in yeast, it seems likely that in the future a
variety of other components will be identified in higher
eukaryotes.
Oligosaccharides Generated in the ER Also Are
Exported to the Cytosol and Degraded
A series of earlier in vitro studies demonstrated that free
oligosaccharides, presumably released from the lipid-linked oligosaccharide involved in the N-glycosylation process, were
2
K. Ro¨misch, personal communication.
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oligosaccharide chain to the peptide, and it thereby would no
longer be detectable as a glycopeptide. In this connection, it is
interesting to note that in mammals there is a system for
transport of small peptides across the membrane of the ER,
which is critical for presentation of the antigenic peptide to the
major histocompatibility class I complex. With respect to the
peptide import mechanism, the transporter associated with
antigen processing (TAP) has been identified (22). It is a member of the ABC (ATP-binding cassette) transporter family that
requires ATP hydrolysis for transporter activity. It is also
known that efflux of small peptides occurs in an ATP-dependent but TAP-independent manner (23, 24), but the relationship
of these processes to the glycopeptide transport system described above remains to be elucidated.
Minireview: Two-way Traffic Across the ER Membrane
10085
FIG. 2. Pathways for formation of
free oligosaccharides in the ER. OSGn2 and OS-Gn1 represent for simplicity
oligosaccharides with N-acetylglucosamine at the reducing terminus whose
complete structure is not defined.
OS-Gn2-PP-Dol 3 OS-Gn2 1 PP-Dol
(I)
OS-Gn2-PP-Dol 3 OS-Gn2P 1 P-Dol
(II)
OS-Gn2-Asn- 3 OS-Gn1 1 Gn-Asnu
u
OS-Gn2-Asn- 3 OS-Gn2 1
Aspu
u
(III)
(IV)
It is clear that oligosaccharides formed in the lumen of the
ER exit from this organelle into the cytosol. Although there are
uncertainties in terms of the detailed structure of the oligosaccharide that is translocated, it is apparent that the process is
ATP-dependent (61). Once in the cytosol, the oligomannosides
may be further processed by the previously described cytosolic
a-mannosidase (57), ENGase (62), and/or chitobiase (63) to
generate GlcNAc1Man5, which is then taken up by lysosomes
and degraded (64, 65). At present it is not known if the cytosolic
ENGase/PNGase and their ER-associated equivalents actually
are the same proteins; so far no clear difference has been
described in terms of enzymatic properties, and it is not clear if
the catalytic site of the ER-associated enzymes is really in the
lumen or exposed on the cytosolic face of the ER membrane.
Key Questions That Remain To Be Answered
It should be clear in this brief overview that the ER is an
incredibly dynamic organelle, with molecules traveling in opposite directions across the lipid bilayer. In the case of the
oligosaccharide-lipids involved in N-glycosylation, this may involve flip-flop of saccharide lipids generated at the cytosolic
face across the membrane to the luminal face of the ER, although we have no idea of the mechanism of this process. We
also do not know why there is translocation of glycoproteins,
glycopeptides, and oligosaccharides in the other direction, i.e.
to the cytosol, rather than transport of these molecules through
the endomembrane system followed by either secretion or degradation after routing to the lysosomes. In the case of unfolded
proteins the conventional route may not be taken because
excessive accumulation of these macromolecules within the
lumen might lead to their aggregation and precipitation,
thereby blocking the secretory pathway. Interestingly, observations made on calreticulin, a luminal glycoprotein that is
Downloaded from http://www.jbc.org/ by guest on November 18, 2014
found to be entrapped in the lumen of microsomes prepared
from a variety of sources (Fig. 2). More recently, the source,
structure, and fate of these oligosaccharides have been studied
by several groups (51). Oligosaccharides of the polymannose type containing either one or two N-acetylglucosamine residues at the reducing end, as well as chains with
or without “capping” glucose residues at the non-reducing end,
have been described. The current model for the mechanism of
formation of free oligosaccharides is more complicated than
had been anticipated in early studies; four possible reactions
leading to free oligosaccharides are shown below. For simplicity, the oligosaccharides are depicted as OS-Gn1, OS-Gn2, or
OS-Gn2-P, where Gn represents GlcNAc at the reducing terminus and OS represents the remainder of the oligosaccharide
chain. One reaction postulated to be involved in their formation
in the ER is a hydrolytic process yielding OS-Gn2 from oligosaccharide-lipid (I). It has been postulated that OST could
function in this hydrolytic process in the absence of -Asn-X-Ser/
Thr- acceptor sites (52), although there is no direct biochemical
evidence that OST can catalyze transfer of oligosaccharide
chains to water instead of to Asn side chains. The second
enzyme that could be responsible for the formation of free
oligosaccharide is a pyrophosphatase that would release OSGn2-P from oligosaccharide-lipid (II). Although this activity
has been reported to be cytosol-oriented in mammalian cells
(53), it has been detected at the luminal face of S. cerevisiae
microsomes (54). Nothing is known about the fate of the oligosaccharide-phosphate produced in this manner. A third route
for oligosaccharide production (III) was hypothesized to be the
result of the action of an endo-b-N-acetylglucosaminidase (ENGase) acting upon N-linked glycoproteins to give rise to OS-Gn1
(55). More recently, a fourth reaction (IV) involving formation
of OS-Gn2 from glycoproteins by the action of a PNGase, which
cleaves the amide bond between the glycosylated Asn residue
and the innermost GlcNAc residue, has been proposed (56, 57).
Indeed, the occurrence of both ENGase and PNGase in an
ER-enriched fraction has been reported (58 – 60).
10086
Minireview: Two-way Traffic Across the ER Membrane
Acknowledgment—We gratefully acknowledge L. Conroy for preparation of the manuscript.
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heat-inducible in Chinese hamster ovary cells (66), are consistent with this idea. When these cells were subjected to heat
stress, calreticulin was found to redistribute; it disappeared
from the ER and appeared in the cytosol (67). Free oligosaccharides and small glycopeptides also are moved out of the cell
by the secretory pathway. In this case, export from the ER to
the cytosol may be necessary in order to prevent their interaction and possible inhibition of other glycosylation-related processes that occur in the ER or the Golgi complex (61).
With respect to the channel involved in the export of oligosaccharides, glycopeptides, and misfolded proteins, little is
known other than the reported involvement of the Sec61p
complex in the retrograde transport of misfolded proteins
(36 –38). It is of interest that transport of all three classes of
compounds appear to have the common feature of requiring
ATP hydrolysis (21, 36, 39, 61). However, it also should be
noted that there are obvious differences in at least some aspects of these transport processes. For instance, under conditions whereby free oligosaccharides can be transported efficiently from the ER to cytosol, glycotripeptide cannot be
transported from the ER in permeabilized HepG2 cells (61).
Finally, it is important to note that many different systems are
under study, and at this stage of our understanding it is by no
means certain that all of these will exhibit the same features.
Clearly, understanding the mechanisms by which movement of
these different classes of molecules, both in and out of the ER,
is regulated offers even greater challenges than envisioned just
a few years ago.
Additions and Corrections
Vol. 273 (1998) 10083–10086
Complex, two-way traffic of molecules across the membrane of the endoplasmic reticulum.
Tadashi Suzuki, Qi Yan, and William J. Lennarz
Page 10085, Fig. 2: Two of the arrows were erroneously labeled. The correct figure is shown below.
FIG. 2
This article appeared in both the April 24, 1998 issue of the Journal and in the 1998 Minireview Compendium.
We suggest that subscribers photocopy these corrections and insert the photocopies at the appropriate
places where the article to be corrected originally appeared. Authors are urged to introduce these
corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of
these corrections as prominently as they carried the original abstracts.
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