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Endoplasmic reticulum: one continuous network compartmentalized by extrinsic cuesTim Levine1 and Catherine Rabouille2
The endoplasmic reticulum (ER) is an extensive three-
dimensional network that stretches from the inner nuclear
envelope to the cell cortex with a single, continuous membrane
and a single, continuous lumen. Yet the ER contains
specialized regions that carry out unique functions. The
question that immediately arises is how the ER can be
compartmentalized if it is continuous, and the answer to this is
that cellular landmarks with unique sub-cellular distributions
impose non-uniformity on the ER from outside, creating
structural and functional sub-domains of the ER.
Addresses1Division of Cell Biology, Institute of Ophthalmology, 11–43 Bath St,
London EC1V 9EL, UK2The Cell Microscopy Centre, Department of Cell Biology and Institute of Biomembranes, University Medical Centre Utrecht, AZU Rm G02.525,
Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
Corresponding author: Rabouille, Catherine ([email protected])
Current Opinion in Cell Biology 2005, 17:362–368
This review comes from a themed issue onMembranes and organelles
Edited by Vivek Malhotra and Mike Yaffe
Available online 21st June 2005
0955-0674/$ – see front matter
# 2005 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.ceb.2005.06.005
IntroductionThe endoplasmic reticulum (ER) is ubiquitous and cells
contain just a single copy. Yet specialized sub-compart-ments of the ER carrying out unique functions can be
distinguished morphologically: the rough ER (RER),
which is studded with ribosomes, and is typically involved
in coupling protein synthesis to protein translocation
into the ER lumen through the translocon; the transi-
tional ER (tER) sites, which are specialized cup-shapedER cisternae from which newly synthesized proteins exit
via COPII vesicles en route to the remainder of the
secretory pathway [1]; and the smooth ER, which is
dedicated to calcium storage and metabolic pathways
involved in drug handling and lipid and steroid synthesis
(reviewed in [2]).
The question that immediately arises is how the ER can
be compartmentalized if it is continuous, and the answer
to this is that cellular landmarks with unique sub-cellular
distributions impose non-uniformity on the ER from
outside, creating ER sub-domains. In some cases, these
extrinsic cues organising the ER are associated withunique structural types of the ER. A clear example of
this is the nuclear envelope, which is organized by
the nuclear material via lamins and lamin receptors.
The notion of extrinsic organization may also apply to
the RER, which is fixed to regions containing ribosomes
[3]. Furthermore, functional heterogeneities within ER
sub-compartments that are not obviously structurally
distinct can also be created by extrinsic cues. Below,
we will discuss some of the recent interesting discoveries
about issues surrounding the nature of the extrinsic
organizer of the ER.
ER positioning imposed by the cytoskeletonPolarity and structure are imparted to cells by the cytos-
keleton, which allows placement of proteins and orga-
nelles in a characteristic relationship to each other.
Therefore, a large degree of the extrinsic organization
of the pan-cellular ER derives from the cytoskeleton. In
many animal cells, the ER is particularly associated with
the microtubules. In the past, ER tubules were found to
be transported on cytoplasmic microtubules predomi-
nantly (but not exclusively) by kinesins, which pull theER from the centre of the cell toward the cell cortex (i.e.
they are plus-end-directed motors). Recently, ER–micro-
tubule associations have been shown to be independentof motors [4,5]. ER–microtubule interactions without a
motor may be important in highly differentiated cells
such as neurons, where large-scale relocation of the ER is
not constitutively required.
The actin cytoskeleton is the major cytoskeletal partner
of the ER in yeast and plant cells, but also plays a role in
animal cells [6]. For instance, the rearrangements of ER
architecture in C. elegans during early embryogenesis have
recently been shown to depend on actin [7]. Therefore, it
is likely that both microtubules and actin control different
aspects of ER positioning and structure.
Organization of tER sitesLittle is known about how tER sites form and maintain
their seemingly random distribution throughout the cell’s
ubiquitous ER. One approach to understanding tERbiogenesis has been to identify the landmark proteins
that recruit the remainder of the tER machinery, much of
this work being carried out in yeast. The COPII subunit
Sec12 was considered to be the tER landmark, until the
COPII subunits Sec23 and Sar1 were shown to concen-
trate into tER sites even after its depletion [8]. Another
candidate is Sec16, a component of the tER sites in yeast,
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fly and human. Depletion or mutation of Sec16 comple-
tely disorganizes tER sites, with failure to recruit Sec23
(Ben Glick, personal communication; and C Rabouille,
unpublished). The final candidate to consider is the Golgi
matrix protein p115, since in Drosophila S2 cells depletion
of the p115 homologue causes an alteration in the orga-nization of the tER sites [9].
Although the biogenesis of the tER is unclear, it is clear
that tER sites are relatively stable structures, in the sense
that they do not move long distances, although they
undergo fission and fusion in both yeast and mammalian
cells [10,11]. Like the rest of the ER, tER sites may be
spatially arranged along microtubules, and a unique rela-
tionship has recently been discovered between Sec23 and
dynactin [12]. It also seems that the tER sites are stablestructures in the sense that they are not generated in
response to protein synthesis and transport. This has been
addressed by live cell imaging using Sec23, VSVG (pro-
tein G from vesicular stomatitis virus) [13], and procolla-
gen [14] tagged with respective fluorescent tags: Sec23
spots did not appear in response to cargo transport in this
system and did not fade away afterwards.
ER non-uniformities derived from localizedmRNA Localization of mRNA is a clear example of how an
extrinsic cue can impose functional non-uniformity onthe RER and tER without being associated with any
obvious structural features. Many mRNAs exhibit a
restricted localization within the cell [15], leading to
restricted protein synthesis, and recent work has shown
that they form particles associated with microtubules[16,17,18]. This is a key mechanism in the establish-
ment of asymmetric protein distribution, f or instance in
cell polarity (reviewed in [16] and [19]). Localized
mRNA codes not only for cytoplasmic proteins, but also
for transmembrane and secreted proteins. For instance,
out of the 22 mRNAs localized to the bud-tip in yeast, at
least five are membrane-associated [20]. The localizedmRNAs encoding transmembrane and secreted proteins
will create heterogeneity within the RER by localized
translation, and heterogeneity among tER sites by loca-
lized transport.
mRNA localization on ER subdomainsTargeting of mRNA to the RER was first discovered in
Xenopus oocytes [21,22]. Different mRNAs can bind
directly to different sub-domains of the RER. For exam-
ple, two mRNAs for membrane proteins are specificallylocalized to different parts of the ER in rice seeds
[23,24]. One mRNA codes for prolamine, which forms
inclusions derived from the ER. The other mRNA codes
for glutein, which is initially translocated into the ER, but
is not found in prolamine inclusions to be transported via
the Golgi apparatus to the vacuole, where it too forms
inclusions. The separate localizations of the mRNAs
minimize mixing of the two proteins and allow the for-
mation of separate inclusions.
Multiple tER–Golgi secretory units
Can localization of mRNAs mediate polarised deposition
or secretion of the resulting protein in just one segment of a cell? This is possible in any cell type that has multiple
tER–Golgi units. This type of exocytic pathway organi-
zation was first described in the yeast Pichia, where each
tER site is close to a Golgi mini-stack, thus forming a
tER–Golgi unit [25]. Similar arrangement of the tER and
Golgi is found in Drosophila cells [9] and Drosophila
oocytes, which are very large cells containing 1000
tER–Golgi units [26], providing a unique system to
study localized protein synthesis.
The Drosophila oocyte is highly polarized. In particular,
secretion of the protein Gurken occurs only at the dorsal–
anterior corner [27]. Gurken is synthesized as a trans-
membrane protein. A cargo-specific co-factor called Cor-
nichon then escorts it rapidly from the ER via the tER to
the Golgi apparatus, where Gurken’s bioactive lumenal
domain is cleaved. Polarized secretion is achieved by
localizing gurken mRNA to the dorsal–anterior corner
of the oocyte, but how does this ensure local secretion?
Firstly, local synthesis leads to local transport because
Cornichon ensures rapid ER transit, greatly limiting
diffusion in the ER, which is continuous here as it is inall cells. Secondly, it appears that each tER–Golgi unit
is able to secrete independently: just 10–15 out of
the 1000 units transport Gurken protein, limiting the
distribution of secreted Gurken (Figure 1b) [26].
This pre-translational mechanism is a previouslyunknown way of creating polarised deposition of trans-
membrane and/or secreted proteins, complementary to
post-translational sorting in the trans-Golgi network
(TGN) [28], and may apply to other secreted proteins
in Drosophila [29].
In mammalian cells, the localisation of mRNAs encodingtransmembrane or secreted proteins has not been system-
atically studied. One reason for this is that past work has
focused in particular on model cargo proteins such as
VSVG being secreted by model cells, often fibroblasts (for
example HeLa cells), where the Golgi apparatus is a
single-copy juxtanuclear ribbon in which all the mini-stacks are linked together [30]. In one cell type, however,
Golgi outposts have been described. These are found in
dendrites of rat neurons, which also contain associated
RER and tER sites [31], and these dendrites are able tosustain local synthesis and transport of transmembrane
proteins, such as the AMPA receptor, independently of
the cell body [32,33]. This is likely to be the result of
translation of localized mRNA (although the AMPA
mRNA has not been formally localized) followed by
transport in these Golgi outposts equivalent to what
occurs in tER–Golgi units. Similar localized translation
Endoplasmic reticulum: one continuous network Levine and Rabouille 363
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and transport is suggested to also take place in axons
[34,35,36].
An additional question yet to be addressed is the extent to
which tER sites are equivalent. That they can function
independently from one another is shown by the local
transport of Gurken protein in Drosophila oocytes
(Figure 1b). However, it is not known whether all the
peripheral tER sites of a HeLa cell are active in the
transport of generic transport markers and it is pos-
sible that these sites are in fact used for the synthesis
of localized, as yet unidentified mRNAs.
364 Membranes and organelles
Figure 1
N
P
mRNA
G tER
site
M
PM
ER
N
Exocyst Lipid transfer protein tSNAREs
Translocon VAP vSNARE
PM
ER
(a)
(b) (c)
(d)
ER heterogeneity is created by extrinsic cues. (a) A diagrammatic representation of the interactions between the ER (green) and different extrinsic
cues including localized mRNAs near peripheral tER sites, the plasma membrane, mitochondria (M) and a phagosome (P). Microtubules are
drawn in purple. G, Golgi apparatus. (b) A single stage-9 Drosophila oocyte surrounded by follicle cells. Within the oocyte, Gurken protein (red)
is restricted to the dorsal/anterior corner near the nucleus (N) in dots representing the tER–Golgi units. The ER in all cells is green. (Courtesy of Bram Herpers, Department of Cell Biology, UMC Utrecht, The Netherlands.) (c) Diagram of three protein complexes potentially involved in
ER–plasma membrane contact [44–47]. (d) Electron micrograph of a mitochondrion wrapped in ER showing zones of apposition (arrows), where
ER depleted of ribosomes comes to within 30nm of the mitochondrion. (Courtesy of Ann de Maziere, Department of Cell Biology, UMC Utrecht,
The Netherlands.) Scale bar represents 200nm.
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ER non-uniformities derived from othermembrane-bound organellesIn addition to the well-known subdomains of the ER (the
RER, smooth ER and tER sites), we address here ER
non-uniformities that are induced by other organelles.
These sub-domains of the ER have no well-describedmorphological features apart from the proximity of other
compartments. The ER is intimately associated with
many other organelles, including the TGN [37], endo-
somes [38], chloroplasts [39] and peroxisomes [40], as well
as with the plasma membrane and the mitochondria,
which we will discuss in greater detail below. The mem-
brane contact sites between the ER and these other
compartments form specialized sub-domains of each
organelle that engage in communication of information
and material across narrow cytoplasmic gaps.
ER and plasma membrane
Cortical ER is closely apposed to a portion of plasma
membrane in all cell types. This proximity has been
supposed to underlie the ability of lipids to traf fic bidir-
ectionally between the ER and the plasma membrane
independently of the secretory pathway [41,42]. Only
in yeast has the portion of the ER attached to the plasma
membrane been purified. In comparison to generic ER it
is enriched in lipid synthases, suggesting that it is adapted
to supply lipids [43].
The physical nature of the ER–plasma-membrane link is
still not certain, but three different bridging complexes
have been characterized recently (Figure 1c). First, in
mammalian cells and yeast, the translocon of RER inter-
acts directly with plasma-membrane-bound exocyst(reviewed in [44]). Further evidence for the significance
of this interaction comes from the recruitment of cortical
ER to the new bud in yeast by the exocyst subunit Sec3
[45]. Second, a conserved ER protein called VAP (VAMP-
associated protein, where VAMP is the v-SNARE vesicle-
associated membrane protein) forms bridging complexes
with peripheral membrane proteins on the plasma mem-brane, as well as other sites in the cell [46]. Third, when
phagocytes engulf large bodies, the plasma membrane
must grow rapidly and under these extreme circum-
stances extra membrane is provided by the ER. This
step is mediated by an ER v-SNARE homologous to
Sec22, the only ER v-SNARE that pairs up with plasmamembrane t-SNAREs [47], implicating direct SNARE-
mediated fusion of the ER with the plasma membrane.
Similarly, stimulation of human lymphocytes induces
contact between the exofacial leaflet of the plasma mem-
brane and the lumenal leaflet of the ER, suggesting the
presence of transient continuity between the ER and the
plasma membrane in these cells [48].
In addition to these ER–plasma-membrane bridges,
there is evidence for membrane traf fic between these
two compartments that bypasses the Golgi apparatus.
The most intriguing data comes from yeast, in which
the polytopic plasma membrane protein Ist2 appears to
traf fic from the cortical ER of the bud-tip (where its
mRNA is specifically localized) to the adjacent plasmamembrane [49]. Presuming that Ist2 is translocated into
the ER, this work suggests that traf fic of Ist2 is indepen-dent of the classical exocytic pathway, as it is unaffected
by a variety of mutations in the secretory pathway
[49,50]. The alternative is that Ist2 might undergo
one of the previously described forms of non-classical
protein secretion (i.e. direct insertion into the plasma
membrane after translation in the cytosol), which hitherto
have mainly been restricted to small secreted cytokines
[51]. The suggestion that direct traf fic occurs between
the ER and the plasma membrane is supported by the
finding that other blocks in the yeast secretory pathwayonly moderately affect the plasma membrane deposition
of the bulk of integral plasma membrane proteins [52].
While it is possible that ER–plasma-membrane contact
sustains a novel traf ficking pathway, it is important to
substantiate this by identifying the molecular machinery
involved, for example by determining whether Ist2 traf fic
requires the SNAREs that pair the ER and the plasma
membrane [47].
ER and mitochondria
The ER and mitochondria are intimately associated witheach other. They are physically linked together in many
cell types, and they co-regulate some highly important
functions, including apoptosis and traf fic of lipids and
Ca2+ [53].
Non-vesicular traffic and the physical link between
the ER and the mitochondria
The specific ER compartment that interacts with the
mitochondria is called the mitochondria-associated ER
membranes (MAM). Very little is known about MAM,
except that it is enriched in many lipid synthases com-
pared to generic ER, and is de-enriched in ribosomes [54].The enrichment of lipid synthases is compatible with one
of the clearest functions of MAM, which is to participate
in lipid traf fic to and from mitochondria [55]. Similarly,
ER sites of Ca2+ release channels appear to be preferen-
tially localized near to mitochondria, implying that MAM
may be specialized for calcium traf fic from the ER to themitochondria [56].
Despite the absence of membrane fusion between the
ER and mitochondria, an emerging theme is that someproteins are shared between these organelles, including
some integral membrane proteins. For these membrane
proteins, post-translational insertion into the mitochon-
dria tends to occur if co-translational insertion into the ER
is inef ficient [57–59]. Importantly, any protein shared
between the ER and the mitochondria that can form
head-to-head dimers is a good candidate for a bridging
Endoplasmic reticulum: one continuous network Levine and Rabouille 365
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component at the zone of apposition (arrows in
Figure 1d). One proposed candidate is the voltage-depen-
dent anion channel (VDAC or ‘porin’) [60], and this may
be an important beginning in mapping the bridging
proteins between MAM and mitochondria, none of which
has been positively identified.
Apoptosis
The ER and mitochondria both control important aspects
of apoptosis, and the pathways involving these two orga-
nelles are highly interdependent. For example, the pro-
apoptotic protein BAP31 resides on the ER and enhances
the pro-apoptotic Ca2+ signal that passes from the ER to
the mitochondria after BAP31 is cleaved by the apoptosis
initiator caspase-8 [61]. Mitochondria are involved in this
cleavage, since caspase 8 is localized on mitochondria andacts in trans to cleave BAP31 on the ER [62]. Thus,
intimate contact between the ER and mitochondria is
important for programmed cell death.
One aspect of this inter-dependence is that the ER and
mitochondria share many apoptotic regulators. This
includes PACS-2, which binds to the proapoptotic
BH3-domain-only protein Bid [63]. In resting cells,
phosphorylated Bid is found both in the cytoplasm and
to some extent on the ER. Following an apoptotic sti-
mulus, Bid is dephosphorylated and then binds to PACS-
2 on mitochondria. Bid is then activated by caspase-8cleavage, forming truncated Bid (tBid), which in turn
induces release of cytochrome c . Interestingly, PACS-2
responds to apoptotic stimuli by translocating from the
ER to mitochondria, and the structure of MAM itself
depends on PACS-2 for its normal integrity [63
],although this may turn out to be a secondary effect of
PACS-2’s role in altering apoptotic pathways. Despite
these exciting findings, we still know very little about how
the portion of ER that is MAM is organized extrinsically
by mitochondria.
ConclusionsThe ER maintains variety in unity. For a long time, the
ER was considered to act in a unified manner, in keeping
with the unitary nature of the rest of the secretory path-
way. However, we now know that localized mRNAs allow
the sub-division of the classical secretory pathway into
separate compartments. In addition, the ER has specificrelationships with many non-ER cellular components,
inducing multiple sub-domains in the ER [64]. For the
sake of brevity, we have only discussed two of these in
detail, the plasma membrane and the mitochondria. Themolecular bridges between the ER and other organelles
are almost entirely undescribed, except in a single case
(the nuclear–vacuole junction in yeast) [65]. In any event,
the idea that extrinsic cues organize the ER leads to a
further question: what provides these cues with their
positional information? The simple answer must be that
the cytoskeleton contains most of the information needed
to organize the different cellular components and their
inter-relationships. In some cases, the molecular mechan-
isms that set up these relationships are now becoming
understood, such as the pathways underpinning the
movement and anchoring of Gurken mRNA [17,18].
However, in most cases of ER sub-compartmentalizationonly a small fraction of the overall mechanism is known at
the molecular level, making this an interesting field to
work in.
AcknowledgementsWe wish to thank Vangelis Kondylis, Judith Klumperman and ChrisLoewen for critically reading this manuscript. We thank Adrian Oprinsfor Figure 1a. Figure 1b and 1d are courtesy of Bram Herpers and Annde Maziere (Utrecht, The Netherlands), respectively. We apologize toour colleagues whose work we have not been able to include because of space constraints.
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This article, together with [34] and [36], exemplifies the interesting andcontroversial possibility that synthesis and transport of transmembraneproteins occurs not only in neuronal cell bodies but also in axons (as indendrites, see [31,32,33] ). Conopressin receptor, for which the mRNA is injected [36], the plasma membrane receptor EphA2, for which themRNA is also injected [34], and Syntaxin [35] are all shown to betranslated and inserted in the plasma membrane independently fromthe cell body.
36. Spencer GE, Syed NI, van Kesteren E, Lukowiak K, Geraerts WP,van Minnen J: Synthesis and functional integration of aneurotransmitter receptor in isolated invertebrate axons. J Neurobiol 2000, 44:72-81.
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38. Haj FG, Verveer PJ, Squire A, Neel BG, Bastiaens PI: Imagingsites of receptor dephosphorylation by PTP1B on thesurface of the endoplasmic reticulum. Science 2002,295:1708-1711.
39. XuC, Fan J,RiekhofW, Froehlich JE, Benning C: A permease-likeproteininvolvedin ER to thylakoid lipid transfer in Arabidopsis.EMBO J 2003, 22:2370-2379.
40. Geuze HJ, Murk JL, Stroobants AK, Griffith JM, Kleijmeer MJ,Koster AJ, Verkleij AJ, Distel B, Tabak HF: Involvement of theendoplasmic reticulum in peroxisome formation. Mol Biol Cell 2003, 14:2900-2907.
41.
Li Y, Prinz WA: ATP-binding cassette (ABC) transportersmediate nonvesicular, raft-modulated sterol movement fromthe plasma membrane to the endoplasmic reticulum . J Biol Chem 2004, 279:45226-45234.
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The traf fic of sterol in yeast is independent of the classical secretorypathway, even though the sterol studied here is cholesterol rather thanendogenous ergosterol. Also, as found in the study by Baumann et al.[42], the propensity for sterol to escape the ER is correlated with itsability to form complexes.
42.
Baumann N, Sullivan D, Ohvo-Rekila ¨ H, Simonot C, Pottekat A,Klaassen Z, Beh C, Menon A: Transport of newly synthesized
sterol to the sterol-enriched plasma membrane occurs vianon-vesicular equilibration. Biochemistry 2005, in press.The kinetics of sterol traf fic to the plasma membrane in yeast are notaffected by blocking all SNARE-mediated traf fic, suggesting that steroltraf fics by a non-vesicular route. Furthermore, sphingolipidsin the plasmamembrane act as a sink for sterol, as together these lipids form high-af finity complexes, so that the total sterol concentration in the plasmamembrane is far higher in than in the ER, although the concentration of free sterol is the same in both compartments.
43. Pichler H, Gaigg B, Hrastnik C, Achleitner G, Kohlwein SD,Zellnig G, Perktold A, Daum G: A subfraction of the yeastendoplasmic reticulum associates withthe plasma membraneand has a high capacity to synthesize lipids . Eur J Biochem2001, 268:2351-2361.
44. Guo W, Novick P: The exocyst meets the translocon: aregulatory circuit for secretion and protein synthesis?Trends Cell Biol 2004, 14:61-63.
45. Wiederkehr A, Du Y, Pypaert M, Ferro-Novick S, Novick P: Sec3pis needed for the spatial regulation of secretion and for theinheritance of the cortical endoplasmic reticulum. Mol Biol Cell 2003, 14:4770-4782.
46. LoewenCJ, Roy A,Levine TP: A conserved ER targeting motif inthree familiesof lipid binding proteins and in Opi1p binds VAP.EMBO J 2003, 22:2025-2035.
47. Becker T, Volchuk A, Rothman JE: Differential use ofendoplasmic reticulum membrane for phagocytosis in J774macrophages. Proc Natl Acad Sci USA 2005, 102:4022-4026.
48. Dadsetan S, Shishkin V, Fomina AF: Intracellular Ca2+ releasetriggers translocation of membrane marker FM1-43 from theextracellular leaflet of the plasma membrane intoendoplasmic reticulum in T lymphocytes. J Biol Chem 2005, inpress.
49.
Juschke C, Ferring D, Jansen RP, Seedorf M: A novel transportpathway for a yeast plasma membrane protein encoded by alocalized mRNA . Curr Biol 2004, 14:406-411.
Transport of the integral membrane protein Ist2 to the plasma membraneis unaffected by various sec mutations inactivating the classical secretorypathway at different points, and appears to rely instead on direct trans-port from the ER to the plasma membrane. In addition, Ist2 mRNA is oneof very few mRNAs localized to the bud-tip that code for a membraneprotein, although the relationship between this and the means of exo-cytosis has not been examined.
50. Juschke C, Wachter A, Schwappach B, Seedorf M: SEC18/NSF-independent, protein-sorting pathway from the yeast corticalER to the plasma membrane. J Cell Biol 2005, in press.
51.
Nickel W: The mystery of nonclassical protein secretion: acurrent view on cargo proteins and potential export routes.Eur J Biochem 2003, 270:2109-2119.
This review describes protein insertion in the plasma membrane that isindependent of the ER. This differs from the novel membrane traf fickingpathway suggested for Ist2 from the ER to the plasma membrane.
52. Schnabl M, Daum G, Pichler H: Multiple lipid transport pathwaysto the plasma membrane in yeast. Biochim Biophys Acta 2005,1687:130-140.
53. Levine T: Short-range intracellular trafficking of smallmolecules across endoplasmic reticulum junctions.Trends Cell Biol 2004, 14:483-490.
54. Wang HJ, Guay G, Pogan L, Sauve R, Nabi IR: Calcium regulatesthe association between mitochondria and a smoothsubdomain of the endoplasmic reticulum. J Cell Biol 2000,150:1489-1498.
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Filippin L, Magalhaes PJ, Di Benedetto G, Colella M, Pozzan T:Stable interactions between mitochondria and endoplasmicreticulum allow rapid accumulation of calcium in asubpopulation of mitochondria. J Biol Chem 2003,278:39224-39234.
Ithasbeenknownforsometime thatCa2+ released from theER canreachhigh local concentrations at mitochondrial Ca2+ uptake pumps, ratherthan being released into the cytoplasm at large. Here, it is shown thatindividual Ca2+ release channels remain physically linked to a specificmitochondrion over reasonably long periods of time, indicating that ER-to-mitochondrion Ca2+ traf fic occurs at stable structures similar to MAM.
57. Colombo S, Longhi R, Alcaro S, Ortuso F, Sprocati T, Flora A,Borgese N: N-myristoylation determines dual targeting ofmammalian NADH-Cytochrome b(5) reductase to ER andmitochondrial outer membranes by a mechanism of kineticpartitioning. J Cell Biol 2005, 168:735-745.
58. Miyazaki E, Kida Y, MiharaK, SakaguchiM: Switching the sorting
mode of membrane proteins from co-translational ERtargeting to post-translational mitochondrial import. Mol Biol Cell 2005, in press.
59. van Herpen RE, Oude Ophuis RJ, Wijers M, Bennink MB,van de Loo FA, Fransen J, Wieringa B, Wansink DG: Divergentmitochondrial and endoplasmic reticulum association ofDMPK splice isoforms depends on unique sequencearrangements in tail anchors. Mol Cell Biol 2005,25:1402-1414.
60. Shoshan-Barmatz V, Zalk R, Gincel D, Vardi N: Subcellularlocalization of VDAC in mitochondria and ER in thecerebellum. Biochim Biophys Acta 2004, 1657:105-114.
61. Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC:Caspase cleavage product of BAP31 induces mitochondrialfission through endoplasmic reticulum calcium signals,enhancing cytochrome c release to the cytosol. J Cell Biol 2003, 160:1115-1127.
62. Chandra D, Choy G, Deng X, Bhatia B, Daniel P, Tang DG: Association of active caspase 8 with the mitochondrialmembrane duringapoptosis: potential roles in cleaving BAP31and caspase 3 and mediating mitochondrion–endoplasmic-reticulum cross talk in etoposide-induced cell death. Mol Cell Biol 2004, 24:6592-6607.
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Simmen T, Aslan JE, Blagoveshchenskaya AD, Thomas L,Wan L, Xiang Y, Feliciangeli SF, Hung CH, Crump CM, Thomas G:PACS-2 controls endoplasmic reticulum-mitochondriacommunication and Bid-mediated apoptosis. EMBO J 2005,24:717-729.
PACS-2, like PACS-1, is shown to be a cargo sorting protein, but unlikePACS-1, which targets cargo within the late secretory pathway, PACS-2targets Bid to mitochondria. Furthermore, PACS-2 is among the firstproteins identified that are essential for normal architecture of ER–mitochondrial-membrane contact sites.
64. StaehelinLA: The plantER: a dynamic organellecomposed of alarge number of discrete functional domains. Plant J 1997,11:1151-1165.
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