The Organizing Potential of Sphingolipids in Intracellular Membrane ...
The Organizing Potential of Sphingolipids in Intracellular Membrane ...
The Organizing Potential of Sphingolipids in Intracellular Membrane ...
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1704 HOLTHUIS, POMORSKI, RAGGERS, SPRONG, AND VAN MEER<br />
cosph<strong>in</strong>golipids. From studies on GalCer <strong>in</strong> myel<strong>in</strong> (199),<br />
GM3 <strong>in</strong> membrane viruses (365, 367), and GM3 and GD1a<br />
<strong>in</strong> a number <strong>of</strong> cells (242) it has been concluded that the<br />
bulk <strong>of</strong> these lipids is situated <strong>in</strong> the noncytoplasmic<br />
surface <strong>of</strong> the plasma membrane (for discussion <strong>of</strong> the<br />
methodology, see Ref. 336).<br />
Still, pools <strong>of</strong> sph<strong>in</strong>golipids may exist on the cytosolic<br />
surface <strong>of</strong> membranes. This is especially true for<br />
GlcCer, which after synthesis is <strong>in</strong>itially present <strong>in</strong> the<br />
cytosolic leaflet <strong>of</strong> the Golgi membrane (65). A cytosolic<br />
prote<strong>in</strong> that can <strong>in</strong>teract with GlcCer has been isolated<br />
from cytosol and its gene cloned (198). Other cytosolic<br />
prote<strong>in</strong>s have been found to be capable <strong>of</strong> <strong>in</strong>teract<strong>in</strong>g with<br />
complex glycosph<strong>in</strong>golipids (49, 54, 134, 135, 243, 352,<br />
353), whereas also glycosph<strong>in</strong>golipids have been colocalized<br />
with cytoskeletal elements (106, 107, 318). 17 This may<br />
suggest that also complex glycosph<strong>in</strong>golipids are present<br />
<strong>in</strong> cytosolic surfaces. This could be a consequence <strong>of</strong> lipid<br />
mix<strong>in</strong>g caused by fission and fusion events dur<strong>in</strong>g membrane<br />
traffic, or <strong>of</strong> transbilayer equilibration <strong>of</strong> a small<br />
sph<strong>in</strong>golipid fraction reach<strong>in</strong>g the ER (see below).<br />
C. Sph<strong>in</strong>golipid Transport and Sort<strong>in</strong>g<br />
1. Concepts<br />
After synthesis, sph<strong>in</strong>golipids can move around the<br />
cell <strong>in</strong> various ways. <strong>Intracellular</strong> transport processes are<br />
fast (m<strong>in</strong>utes) compared with sph<strong>in</strong>golipid turnover<br />
(many hours). So, to ma<strong>in</strong>ta<strong>in</strong> the differences <strong>in</strong> sph<strong>in</strong>golipid<br />
concentration between cellular membranes, there<br />
must be specificity <strong>in</strong> sph<strong>in</strong>golipid transport. We recently<br />
discussed sph<strong>in</strong>golipid transport <strong>in</strong> a separate review<br />
(397). <strong>The</strong> present paper focuses on the specificity <strong>in</strong><br />
sph<strong>in</strong>golipid transport and the <strong>in</strong>volvement <strong>of</strong> sph<strong>in</strong>golipids<br />
<strong>in</strong> sort<strong>in</strong>g other membrane components.<br />
When situated <strong>in</strong> a membrane, sph<strong>in</strong>golipids first <strong>of</strong><br />
all can diffuse as monomers <strong>in</strong> four directions. If we do<br />
not take <strong>in</strong>to account the motions <strong>of</strong> the entire molecule<br />
that do not result <strong>in</strong> transport, like the rotation around<br />
their longitud<strong>in</strong>al axis and the wobble (279), sph<strong>in</strong>golipids<br />
can diffuse laterally <strong>in</strong> the two-dimensional plane <strong>of</strong> the<br />
membrane; they can diffuse out <strong>of</strong> the membrane <strong>in</strong>to the<br />
aqueous phase, and they can flip across the membrane<br />
<strong>in</strong>to the opposite lipid monolayer. 18 Of these movements,<br />
17 Because the cells had been treated with acetone and/or TX-100<br />
before antibody addition, it is possible that these lipids were orig<strong>in</strong>ally<br />
present on the lum<strong>in</strong>al side <strong>of</strong> cytosolic vesicles or vacuoles.<br />
18 Diffusion <strong>in</strong>to the opposite leaflet <strong>of</strong> the bilayer without a<br />
change <strong>in</strong> the longitud<strong>in</strong>al orientation <strong>of</strong> the molecule, by which the<br />
molecule merely dips deeper <strong>in</strong>to the membrane, is followed by movement<br />
back to its orig<strong>in</strong>al position, without consequences for transport.<br />
Only transversal diffusion plus rotation around one <strong>of</strong> its short axes, by<br />
which the head group changes orientation, flips the molecule <strong>in</strong>to the<br />
Physiol Rev • VOL 81 • OCTOBER 2001 • www.prv.org<br />
only diffusion out <strong>of</strong> the membrane may result <strong>in</strong> transport<br />
between cellular organelles. <strong>The</strong> second mechanism<br />
<strong>of</strong> lipid transfer <strong>in</strong> cells is by the vesicular transport<br />
pathways that connect most cellular organelles. F<strong>in</strong>ally,<br />
lipids may be transported between organelles via transient<br />
contacts between the membranes <strong>of</strong> the two organelles.<br />
19<br />
<strong>The</strong> word sort<strong>in</strong>g is used to <strong>in</strong>dicate the process by<br />
which the cell generates the differences <strong>in</strong> prote<strong>in</strong> and<br />
lipid composition between two membranes, start<strong>in</strong>g from<br />
a membrane where these components were mixed. Because<br />
the <strong>in</strong>tracellular traffic is practically a closed system<br />
for membrane components, the term generates is<br />
equivalent to the term ma<strong>in</strong>ta<strong>in</strong>s. Where transport between<br />
membranes occurs by aqueous diffusion <strong>of</strong> a certa<strong>in</strong><br />
component as monomers, sort<strong>in</strong>g requires a different<br />
aff<strong>in</strong>ity <strong>of</strong> this component for the two membranes. This<br />
may concern the aff<strong>in</strong>ity <strong>of</strong> the component for other membrane<br />
components, or, theoretically, the aqueous diffusion<br />
could be made unidirectional by transfer prote<strong>in</strong>s. 20<br />
In vesicular transport pathways, bidirectional transport <strong>of</strong><br />
vesicles <strong>of</strong> random composition would result <strong>in</strong> mix<strong>in</strong>g <strong>of</strong><br />
all components and dissipation <strong>of</strong> differences between<br />
the two compartments. In this case sort<strong>in</strong>g requires preferential<br />
<strong>in</strong>clusion <strong>of</strong> a specific component <strong>in</strong> the budd<strong>in</strong>g<br />
vesicle <strong>in</strong> at least one <strong>of</strong> the two compartments. This<br />
means lateral concentration <strong>of</strong> this component and locat<strong>in</strong>g<br />
the site <strong>of</strong> higher concentration to the site <strong>of</strong> vesicle<br />
budd<strong>in</strong>g.<br />
2. Monomeric transport through the cytosol<br />
<strong>The</strong> rate <strong>of</strong> monomeric diffusion <strong>of</strong> a sph<strong>in</strong>golipid<br />
between two membranes strongly depends on its physical<br />
structure. <strong>The</strong> smaller the hydrophobic part, and the<br />
larger or more polar the hydrophilic part, the higher the<br />
rate <strong>of</strong> exchange. Sph<strong>in</strong>goid bases and their phosphory-<br />
opposite membrane leaflet. <strong>The</strong> degree <strong>of</strong> wobble experienced by a lipid<br />
<strong>in</strong> a certa<strong>in</strong> membrane is clearly one parameter that determ<strong>in</strong>es the flip<br />
rate. Other parameters are the size and polarity <strong>of</strong> the polar head group<br />
and the dielectric constant <strong>of</strong> the membrane <strong>in</strong>terior.<br />
19 <strong>Membrane</strong>s may come <strong>in</strong>to close proximity, which stimulates<br />
monomeric exchange though the aqueous phase by enhanc<strong>in</strong>g the desorption<br />
from the membrane (treated <strong>in</strong> detail <strong>in</strong> Ref. 39). <strong>The</strong> cytosolic<br />
monolayers <strong>of</strong> the two organelles may transiently become cont<strong>in</strong>uous<br />
(hemi-fusion), or transient fusion between the apposed membranes may<br />
occur. <strong>The</strong> last possibility can be considered a special case <strong>of</strong> vesicular<br />
traffic.<br />
20 In an <strong>in</strong> vitro study <strong>in</strong> a mixture <strong>of</strong> ER and plasma membrane,<br />
cholesterol preferentially partitioned <strong>in</strong>to the plasma membrane, which<br />
is thought to be due to its high aff<strong>in</strong>ity for the sph<strong>in</strong>golipids abundant <strong>in</strong><br />
plasma membranes (408; for a review see Ref. 203). On the other hand,<br />
transfer prote<strong>in</strong>s might pick up a lipid from one membrane and deliver<br />
it to another membrane after be<strong>in</strong>g modified by, e.g., phosphorylation at<br />
that target membrane. <strong>The</strong> activated prote<strong>in</strong> would then leave the membrane<br />
empty, be <strong>in</strong>activated at the donor membrane, and start a new<br />
round <strong>of</strong> delivery. No experimental support for this mechanism exists.