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

736 Chapter 13: Intracellular Membrane Traffic
Early endosomes have tubular and vacuolar domains (see Figure 13–53). Most
of the membrane surface is in the tubules and most of the volume is in the vacuolar
domain. During endosome maturation, the two domains have different fates: the
vacuolar portions of the early endosome are retained and transformed into late
endosomes; the tubular portions shrink. Maturing endosomes, also called multivesicular
bodies, migrate along microtubules toward the cell interior, shedding
membrane tubules and vesicles that recycle material to the plasma membrane
and TGN, and receiving newly synthesized lysosomal proteins. As they concentrate
in a perinuclear region of the cell, the multivesicular bodies fuse with each
other, and eventually with endolysosomes and lysosomes (see Figure 13–47).
Many changes occur during the maturation process. (1) The endosome changes
shape and location, as the tubular domains are lost and the vacuolar domains are
thoroughly modified. (2) Rab proteins, phosphoinositide lipids, fusion machinery
(SNAREs and tethers), and microtubule motor proteins all participate in a molecular
makeover of the cytosolic face of the endosome membrane, changing the
functional characteristics of the organelle. (3) A V-type ATPase in the endosome
membrane pumps H + from the cytosol into the endosome lumen and acidifies the
organelle. Crucially, the increasing acidity that accompanies maturation renders
lysosomal hydrolases increasingly more active, influencing many receptor–ligand
interactions, thereby controlling receptor loading and unloading. (4) Intralumenal
vesicles sequester endocytosed signaling receptors inside the endosome,
thus halting the receptor signaling activity. (5) Lysosome proteins are delivered
from the TGN to the maturing endosome. Most of these events occur gradually
but eventually lead to a complete transformation of the endosome into an early
endolysosome.
In addition to committing selected cargo for degradation, the maturation process
is important for lysosome maintenance. The continual delivery of lysosome
components from the TGN to maturing endosomes, ensures a steady supply of
new lysosome proteins. The endocytosed materials mix in early endosomes with
newly arrived acid hydrolases. Although mild digestion may start here, many
hydrolases are synthesized and delivered as proenzymes, called zymogens, which
contain extra inhibitory domains that keep the hydrolases inactive until these
domains are proteolytically removed at later stages of endosome maturation.
Moreover, the pH in early endosomes is not low enough to activate lysosomal
hydrolases optimally. By these means, cells can retrieve membrane proteins
intact from early endosomes and recycle them back to the plasma membrane.
ESCRT Protein Complexes Mediate the Formation of Intralumenal
Vesicles in Multivesicular Bodies
As endosomes mature, patches of their membrane invaginate into the endosome
lumen and pinch off to form intralumenal vesicles. Because of their appearance in
the electron microscope such maturing endosomes are also called multivesicular
bodies (Figure 13–54).
The multivesicular bodies carry endocytosed membrane proteins that are to
be degraded. As part of the protein-sorting process, receptors destined for degradation,
such as the occupied EGF receptors described previously, selectively partition
into the invaginating membrane of the multivesicular bodies. In this way,
both the receptors and any signaling proteins strongly bound to them are sequestered
away from the cytosol where they might otherwise continue signaling.
They also are made fully accessible to the digestive enzymes that eventually will
degrade them (Figure 13–55). In addition to endocytosed membrane proteins,
multivesicular bodies include the soluble content of early endosomes destined
for late endosomes and digestion in lysosomes.
As discussed earlier, sorting into intralumenal vesicles requires one or multiple
ubiquitin tags, which are added to the cytosolic domains of membrane proteins.
These tags initially help guide the proteins into clathrin-coated vesicles in
the plasma membrane. Once delivered to the endosomal membrane, the ubiquitin
tags are recognized again, this time by a series of cytosolic ESCRT protein
intralumenal
vesicle
multivesicular
body
0.5 µm
Figure 13–54 Electron micrograph of a
multivesicular body. The large amount
of internal membrane will be delivered to
the lysosome, MBoC6 for m13.55/13.55
digestion. (Courtesy of
Andrew Staehelin, from A. Driouich,
A. Jauneau and L.A. Staehelin; Plant
Physiol. 113:487–492, 1997. With
permission from the American Society of
Plant Biologists.)