Differential ER exit in yeast and mammalian cells
Reika Watanabe and Howard Riezman1
The coat complex COPII forms vesicles at the endoplasmic
reticulum to transport a variety of cargo proteins to the Golgi
structure. Recent biochemical and structural studies reveal the
molecular mechanism of cargo protein recognition by COPII
components. Furthermore, there are at least two distinct
ER-to-Golgi transport carrier structures carrying different
cargo proteins in yeast and mammalian cells, suggesting
several distinct mechanisms for the concentration, selection
and exit of cargo proteins from the ER. It will be essential to
follow the dynamics of transitional ER sites and cargo protein
concentration within the ER in order to understand how these
transport processes occur in living cells.
Addresses
Department of Biochemistry, University of Geneva, Sciences II, 30,
quai E. Ansermet, CH-1211 Geneva 4, Switzerland
1
e-mail: [email protected]
Current Opinion in Cell Biology 2004, 16:350–355
This review comes from a themed issue on
Membranes and organelles
Edited by Judith Klumperman and Gillian Griffiths
Available online 19th June 2004
0955-0674/$ – see front matter
ß 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.ceb.2004.06.010
Abbreviations
ER
endoplasmic reticulum
COG
conserved oligomeric Golgi
COP
coat protein complex
GPI
glycosylphosphatidylinositol
GPI-protein glycosylphosphatidylinositol-anchored protein
PC
procollagen
tER
transitional ER
Introduction
Proteins of the secretory pathway are synthesized and
inserted into the ER from where they are transported to
their final destination. This process requires an efficient
and selective mechanism for the exit of cargo proteins
from the ER. In addition, the existence of distinct
ER-derived vesicles or tubular structures for different
cargo proteins traveling from the ER have been shown.
Morphological studies show that transitional ER sites
function in the process of ER-to-Golgi protein transport.
In this review, we focus on interesting new findings
concerning the exit mechanism of cargo proteins from
the ER, cargo protein sorting in the ER and the role of
transitional ER sites for these processes.
Current Opinion in Cell Biology 2004, 16:350–355
Exit mechanism of cargo proteins
To leave the ER efficiently after the completion of proper
folding and modification, most proteins are concentrated
into ER-derived vesicles. However, some very abundant
soluble proteins like amylase and chymotrypsinogen are
concentrated at a later stage in the secretory pathway via
their exclusion from retrograde vesicles [1]. COPII components are responsible for the ER exit of most proteins
[2]. At this step there must be a mechanism to distinguish
between ER resident proteins and properly folded cargo
proteins. What is known about ER export signals? How
are various cargo proteins recognized for integration into
COPII-coated vesicles? How are soluble proteins efficiently packaged into ER-derived carriers?
Direct interaction between COPII components and ER
export motifs on the transmembrane cargo proteins
Several mammalian and yeast proteins exit the ER
efficiently because they possess an ER exit signal [3,4]
(see Table 1). Two classes of ER export signals, di-acidic
motifs and di-hydrophobic motifs, have been found on
the C termini of type I transmembrane proteins. Both
motifs participate in a Sar1p-dependent binding to the
Sec23p–Sec24p complex. Recently, a third class of ER
export motif, di-basic motifs, were discovered in the
cytoplasmic tail of type II membrane proteins, i.e.
Golgi-resident glycosyltransferases [5]. The di-basic
motif is located proximal to the transmembrane domain,
and directly interacts with the COPII component Sar1p
[5]. On the basis of current experimental data, the Sec24
protein family seems to make the greatest contribution to
cargo recognition. Using sec24 mutants in an in vitro
budding assay, it was demonstrated that Sec24 proteins
contain multiple independent cargo recognition sites [6].
In addition, the fact that Sec24 proteins have two homologs in yeast and at least four homologs in higher eukaryotes suggests a rather large capacity to bind various ER
export motifs, including some which are not yet identified. For example, the Pma1 protein requires a Sec24
homolog, Lst1p, for efficient packaging [7]. Recent studies on the recognition of SNARE molecules by the
Sec23p–Sec24p complex reveal three binding sites on
the complex that are involved in binding to distinct motifs
on the SNARE molecules [6,8]. Furthermore, as
t-SNARE assembly exposes a hidden binding motif on
Sed5p, the selective binding of Sec23p-Sec24p complex
to the SNARE complex is favored. This regulated binding mechanism may be important for the fusion specificity of vesicles generated in vivo. Several studies imply
that Sar1p might also contribute directly to cargo recognition [3,9]. The Rab-GTPase Ypt1p may also be involved
in cargo selection (see below in the section ‘‘Differential
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Differential ER exit in yeast and mammalian cells Watanabe and Riezman 351
Table 1
Mechanism of concentration during exit from the ER.
Protein
Signals
Transmembrane cargo proteins
VSV-G
Emp24p
GalT2
Soluble or lumenal proteins
Diacidic (YTDIE)
Dihydrophobic (FF, LV)
Dibasic (RR)
Preproalphafactor
Gas1p
Misfolded or improper or orphan subunit protein
(Destined for cytosolic ubiquitin protease system
after retrotranslocation into cytosol)
Sec61-2p
Unknown
Unknown
CPY
Carbohydrate-based retention
mechanism exposed
hydrophobic patch
Unknown
ER exit or retrotranslocation
mechanism
Reference
Direct recognition by COPII
components
[3,4]
Mediated by transmembrane
receptor
Erv29p
Emp24p-complex dependent
[3]
[10]
[11]
[22,23]
Does not require functional
ER to Golgi transport
Requires functional ER to
Golgi transport
Bold letters indicate known key residues.
ER exit of GPI anchored proteins and non-GPI-anchored
proteins in yeast’’).
Cargo receptor proteins
In the case of the soluble cargo proteins, which are
localized to the lumen, one could imagine that transmembrane receptor proteins could be involved in cargo
recognition or concentration. So far, some putative transmembrane cargo receptors, such as yeast Erv29p [10] and
the conserved p24 family [11], have been shown to be
involved in concentration of lumenally localized proteins.
However, the particular exit motifs for these lumenal
cargoes have not yet been identified.
Cargo oligomerization and aggregation
Oligomerization or assembly of cargo proteins is clearly
important for the ER exit of many cargo proteins, including the arginine permease Can1p, an ATP-binding cassette transporter Yor1p, the SNARE molecules described
above, the Erv41–Erv46p complex and Emp46–Emp47p
[3]. By contrast, it was reported that oligomerization is not
important for the efficient incorporation of the yeast
plasma membrane Hþ-ATPase Pma1p into ER-derived
vesicles in vitro [12]. However, in this study, the in vitro
budding assay for Pma1p was carried out using non-hydrolysable GTP (GMP–PNP). A subsequent study showed
that GTP hydrolysis by Sar1p is important for the detection of dependence on an oligomeric state for cargo loading
into vesicles [9]. Therefore, one has to be careful when
interpreting studies using non-hydrolysable GTP to investigate the selective budding of cargo proteins.
In summary, there are clearly different avenues for recognition of cargo proteins. Recognition can be by direct
interaction between the coat protein and an individual
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cargo molecule or receptor protein, but, for some proteins,
can depend upon proper oligomerization and/or assembly
of those proteins. Dependence upon oligomerization for
binding to coat components may be a mechanism to
ensure that only functional cargo complexes exit from
the ER.
Cargo protein sorting
In yeast, at least two kinds of ER vesicles, one containing
glycosylphosphatidylinositol-anchored proteins (GPIproteins) and another containing several secretory proteins, have been identified. In mammalian cells, large
protein aggregates such as procollagen and other small
diffusible cargo proteins are incorporated into distinct ER
carrier structures. These results provide strong evidence
for sorting of cargo proteins in the ER. So far the biological significance of this sorting step is under discussion.
How is sorting achieved at the level of the ER?
Differential ER exit of GPI-anchored proteins and
non-GPI-anchored proteins
ER-derived vesicles containing GPI-proteins can be
separated from other ER-derived vesicles by immunoisolation techniques and by flotation in sucrose-density
gradients [13]. Several known components of the cytosol
and membrane have been shown to be required for this
cargo sorting step [14,15]. One functional group of these
proteins is the tethering factors, comprising the yeast
homologue of mammalian p115, Uso1p, and the conserved oligomeric Golgi (COG) complex, previously
called the Sec34/35 complex. These tethering factors are
thought to be involved in the initial recognition between
the vesicles and acceptor membranes before SNARE
pairing. In an in vitro assay that reconstituted the ERderived vesicle budding from mutant cells defective in
Current Opinion in Cell Biology 2004, 16:350–355
352 Membranes and organelles
tethering proteins, GPI-proteins and non-GPI-proteins
were incorporated into the same ER-derived vesicles,
indicating that the sorting of the cargoes is defective in
these cells. This sorting function is not dependent on the
tethering function, because a Golgi-localized tethering
factor, the TRAPP complex, is not required for this
sorting step. The Rab GTPase Ypt1p is also involved
in this sorting step. The Rab GTPase family is known to
be involved in determining the specificity of vesicle
targeting to the proper acceptor membrane. A possible
scenario coupling cargo protein sorting and vesicle targeting involves Ypt1p targeting Uso1p and the COG complex to the ER where sorting, packaging and budding
occur [14,16]. The coupling of cargo protein sorting to
vesicle targeting could ensure specificity in the secretory
pathway. In addition to these tethering factors, ER
v-SNAREs, but not Golgi t-SNAREs, are required for
GPI-anchored protein sorting [15] (Figure 1). In one ER
v-SNARE mutant, bos1-1, Golgi maturation of GPIprotein Gas1p was specifically affected, but Gas1p still
reached the plasma membrane. These results show that
ER v-SNAREs are part of the cargo protein sorting
machinery upon exit from the ER and suggest that a
correct sorting process may be necessary for proper
maturation of GPI-proteins [15]. Even though several
factors involved in sorting GPI-proteins from non-GPIproteins are known, the mechanism of sorting, how it is
regulated, and the sorting determinants for GPI-proteins
are not known. GPI-proteins are partially associated with
detergent-insoluble membrane fractions (so-called rafts)
[17]. This association could partly contribute to the
sorting of GPI-proteins upon exit from the ER. The
availability of an in vitro assay to reconstitute this sorting
step is useful for the further understanding of sorting
mechanism [14].
Two types of ER-to-Golgi carriers in mammalian cells
In mammalian cells as well as in yeast cells, it seems that
there are different carriers transporting cargoes from the
ER to the Golgi apparatus [18]. It has been shown that a
large macromolecular cargo, procollagen (PC) I, is incorporated into a carrier structure distinct from those carrying other transmembrane cargo proteins, such as VSVG, a
viral membrane glycoprotein, or ERGIC53, in Vero and
HeLa cells [18]. These segregation events require COPI
function, either directly or indirectly. By contrast, analysis
using electron microscopy and tomography reveals that
while PC I and VSVG are concentrated in different
domains of the ER, both are close to ER exit sites
(labeled with antibodies against Sec23p; see section on
‘‘Transitional ER sites and COPII vesicle formation’’)
and both move to the Golgi by the same transport carrier
in human fibroblasts [19]. However, in this case, as the
first time point is four minutes after release from the ER,
it is not clear whether they are primarily incorporated into
the same transport carrier or first incorporated into distinct ER carriers and colocalize only after fusion of two
carriers. Nevertheless, it seems that there is segregation at
Figure 1
Separation
of cargo
ER
ER
Concentration and vesicle formation
ER
Transitional
ER sites
GPI- anchored protein
Non GPI-anchored protein
Current Opinion in Cell Biology
A model for GPI-protein sorting. A model for the sorting of GPI-protein in the ER in yeast is shown. v-SNAREs, Rab GTPase Ypt1, and several
tethering factors are required for the sorting step of GPI-proteins and non-GPI-proteins. These proteins are incorporated into distinct
ER-derived vesicles in COPII-dependent manner. Electron microscopic analysis shows that these proteins are concentrated in the different
regions in the ER [15], but whether these regions are either inside or close to the transitional ER sites is not yet clear.
Current Opinion in Cell Biology 2004, 16:350–355
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Differential ER exit in yeast and mammalian cells Watanabe and Riezman 353
least at the level of the ER for different cargoes in
mammalian cells as well. The segregation in the ER
may be due to the different concentration mechanisms
of the cargo proteins: VSVG contains a motif that binds
directly to Sec23p–Sec24p complex, whereas PC I is a
large lumenal aggregate that may or may not have a
receptor. Another important issue that still needs to be
resolved is whether the first ER-to-Golgi transport carrier
is a vesicular or tube-like structure in mammalian cells. In
the same study, microinjection of a Sar1p dominantnegative mutant inhibited VSV.G and PCI carrier tubule
formation, but microinjection of anti-NSF antibody, antip97 antibody and a-SNAP dominant negative mutant
protein did not affect the exit of VSV.G from the ER.
The authors claimed that formation of tubules carrying
both proteins is COPII-dependent but does not depend
upon the budding of COPII vesicles, because VSV.G was
found in large structures and there was no accumulation
of VSVG positive vesicles even in the presence of the
microinjected inhibitors of membrane fusion. However,
virtually nothing is known about the process of homotypic
fusion of ER-derived vesicles. Therefore, it is not possible to know if microinjection of these inhibitors blocked
the process. For example, it remains possible that NSF
and p97 have a redundant role in homotypic vesicle
fusion. If this were the case, then homotypic vesicle
fusion would not have been blocked by microinjection
of inhibitors as carried out in this study.
between the ER and the Golgi compartment is necessary
for degradation of soluble misfolded proteins. Second,
they could be directly degraded by a Golgi-associated
degradation system [26]. Finally, the degradation of
soluble misfolded substrates might simply require a fully
functional ER compartment that becomes damaged due
to the transport block [25]. To understand how abnormal
proteins are recognized and destined for the degradation
pathway, it is important understand the ER exit and the
sorting mechanism of cargo proteins.
Transitional ER sites and COPII vesicle
formation
Several studies have shown that the ER lumen is continuous, but morphologically and functionally ER membranes have several structural domains. Some of these
specialized domains have been identified morphologically, but specific proteins, for example in lipid and
glycolipid metabolism, have been localized to such microdomains. Specialized ER microdomains include the
nuclear envelope, rough and smooth ER and the regions
that form contacts with other organelles, such as the
plasma membrane, the trans-Golgi compartment, peroxisomes, the vacuole (in yeast) and the mitochondria
[27–29]. These domains are likely to fulfill specialized
functions. The transitional ER (tER) site is also an ER
subdomain where COPII components are concentrated
and that is specialized for COPII transport vesicle formation [2].
ER quality control and ER-to-Golgi transport
Recently, a gene involved in deacylation of the inositol
moiety of GPI-proteins was identified in mammalian cells
[20]. The mutant cells did not have a GPI-anchoring
defect, but the maturation of GPI-anchored proteins was
significantly delayed. The corresponding yeast mutants,
bst1/per17-1, also showed slow GPI-protein maturation
[21]. It needs to be determined whether the slow maturation is due to a defect in exit from the ER or to a
modification in the Golgi structure. Interestingly, this
yeast mutant cell was identified by a defect in degradation
of soluble misfolded proteins [21]. Normally, misfolded
proteins or orphan subunit proteins are retained in the ER
and retrotranslocated into the cytoplasm where they are
degraded by the ubiquitin–proteasome system [22,23].
The fact that both the ER exit of GPI-proteins and ER
degradation seem to be disturbed in the bst1 mutant
suggests the possibility that GPI-protein exit and the
degradation of misfolded soluble proteins could share a
common mechanism, perhaps involving exit from the ER.
Several groups have data suggesting that degradation of
soluble misfolded proteins requires functional ER-toGolgi transport [21,24,25]. So far there are several possible
explanations for the delay in degradation of soluble misfolded protein in the ER-to-Golgi transport mutant cells.
One possibility is that the soluble misfolded proteins
need to be modified at the Golgi apparatus and returned
to ER to be degraded or that cycling of unknown factors
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Dymamics and formation of tER sites
Recent studies that visualized tER sites in mammalian
cells [30] and the budding yeast Pichia pastoris [31]
showed that they are rather stable structures and form
de novo. The Sec12 protein has been proposed to organize
tER sites. As Sec12p is excluded from budding COPII
vesicles, it is a good candidate to maintain the stability of
tER sites. The de novo formation of tER sites suggests
that the tER components have a self-associating capacity,
and nucleation of these components may induce formation of new tER exit sites. Clearly, it is important to
understand how tER sites contribute to COPII vesicle
formation and the concentration of cargo.
Contribution of tER sites to cargo concentration
What is the precise function of tER sites in the formation
of vesicular or tubular carrier structures? A recent morphological study shows that cargo proteins such as VSVG
and PC I are concentrated in the domain very close to but
not inside the tER sites, which seems to protrude directly
from the ER to form ER-to-Golgi carrier structures [19].
This, together with the fact that tER sites are quite stable
structures, led to the proposition that tER sites function
to concentrate cargo proteins and to store proteins of the
fusion machinery (SNAREs) through binding to COPII
[19]. A combination of biochemical and morphological
studies into the relationship between tER sites and carrier
Current Opinion in Cell Biology 2004, 16:350–355
354 Membranes and organelles
structure formation will be necessary for further understanding of the involvement of tER membrane domains
in ER-to-Golgi transport.
Conclusions
In the past few years it has become clear that there are
multiple mechanisms and pathways for cargo proteins to
exit the ER in both yeast and mammalian cells. One
might ask about the reasons for having these two pathways. Our currently favored explanation for this is that it
functions to separate different cargoes upon ER exit to
prevent interactions between the distinct cargoes. For
instance, in yeast cells, several of the GPI-proteins are
proteases and they could have an adverse effect if found
together in vesicles with other secretory proteins. In
mammalian cells, one of the pathways seems to be specialized to transport large aggregates. Evidently, these
aggregates would not fit in a small COPII-coated vesicle.
However, the separation of pathways may also serve to
prevent other proteins from being incorporated into these
protein aggregates upon their formation. Hopefully, in the
near future we will learn more about the mechanisms and
reasons for cargo protein sorting upon exit from the ER.
Acknowledgements
Studies in Howard Riezman’s laboratory are supported by a grant from
Swiss National Foundation and a Human Frontier Science Program
long-term fellowship (to R Watanabe).
References and recommended reading
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review, have been highlighted as:
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