Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

TRANSPORT INTO THE CELL FROM THE PLASMA MEMBRANE: ENDOCYTOSIS
737
signaling
receptor
(with ligand
attached)
ubiquitin
tag
early
endosome
maturing
endosome
free
ubiquitin
INVAGINATION
AND PINCHING OFF
(SEQUESTRATION)
lysosomal protease
intralumenal
vesicle
multivesicular
body
lysosomal hydrolases
FUSION
late endosome
or lysosome
endolysosome
complexes, (ESCRT-0, -I, -II, and -III), which bind sequentially and ultimately
mediate the sorting process into the intralumenal vesicles. Membrane invagination
into multivesicular bodies also depends on a lipid kinase that phosphorylates
phosphatidylinositol to produce PI(3)P, which serves as an additional docking site
for the ESCRT complexes; these complexes require both PI(3)P and the presence
of ubiquitylated cargo proteins to MBoC6 bind m13.57/13.56
to the endosomal membrane. ESCRT-III
forms large multimeric assemblies on the membrane that bend the membrane
(Figure 13–56).
Mutant cells compromised in ESCRT function display signaling defects. In
such cells, activated receptors cannot be down-regulated by endocytosis and
packaging into multivesicular bodies. The still-active receptors therefore mediate
prolonged signaling, which can lead to uncontrolled cell proliferation and cancer.
Processes that shape membranes often use similar machinery. Because of
strong similarities in their protein sequences, researchers think that ESCRT complexes
are evolutionarily related to components that mediate cell-membrane
deformation in cytokinesis in archaea. Similarly, the ESCRT machinery that
drives the internal budding from the endosome membrane to form intralumenal
vesicles is also used in animal cell cytokinesis and virus budding, which are topologically
equivalent, as both processes involve budding away from the cytosolic
surface of the membrane (Figure 13–57).
Recycling Endosomes Regulate Plasma Membrane Composition
The fates of endocytosed receptors—and of any ligands remaining bound to
them—vary according to the specific type of receptor. As we discussed, most
receptors are recycled and returned to the same plasma membrane domain from
which they came; some proceed to a different domain of the plasma membrane,
thereby mediating transcytosis; and some progress to lysosomes, where they are
degraded.
Receptors on the surface of polarized epithelial cells can transfer specific
macromolecules from one extracellular space to another by transcytosis. A newborn,
for example, obtains antibodies from its mother’s milk (which help protect
it against infection) by transporting them across the epithelium of its gut. The
lumen of the gut is acidic, and, at this low pH, the antibodies in the milk bind
to specific receptors on the apical (absorptive) surface of the gut epithelial cells.
The receptor–antibody complexes are internalized via clathrin-coated pits and
CYTOSOL
LUMEN OF
ENDOSOME
PI(3)P
ESCRT-0 ESCRT-I ESCRT-II ESCRT-III
P
ubiquitin
cargo
forming intralumenal
vesicle
endosome
membrane
Figure 13–55 The sequestration of
endocytosed proteins into intralumenal
vesicles of multivesicular bodies.
Ubiquitylated membrane proteins are
sorted into domains on the endosome
membrane, which invaginate and pinch
off to form intralumenal vesicles. The
ubiquitin marker is removed and returned
to the cytosol for reuse before the
intralumenal vesicle closes. Eventually,
proteases and lipases in lysosomes
digest all of the internal membranes.
The invagination processes are essential
for complete digestion of endocytosed
membrane proteins: because the outer
membrane of the multivesicular body
becomes continuous with the lysosomal
membrane, which is resistant to lysosomal
hydrolases; the hydrolases, for example,
could not digest the cytosolic domains of
endocytosed transmembrane proteins,
such as the EGF receptor shown here,
if the protein were not localized in
intralumenal vesicles.
Figure 13–56 Sorting of endocytosed
membrane proteins into the intralumenal
vesicles of a multivesicular body.
A series of complex binding events
passes the ubiquitylated cargo proteins
sequentially from one ESCRT complex
(ESCRT-0) to the next, eventually
concentrating them in membrane areas
that bud into the lumen of the endosome
to form intralumenal vesicles. ESCRT‐III
assembles into expansive multimeric
structures and mediates invagination. The
mechanisms of how cargo molecules are
shepherded into the vesicles and how the
vesicles are formed without including the
ESCRT complexes themselves remain
unknown. ESCRT complexes are soluble in
the cytosol, are recruited to the membrane
sequentially as needed, and are then
released back into the cytosol as the
vesicle pinches off.