The exact fate of the receptor in the membrane appears to vary
with the cell. It can also be degraded. However, some receptors move
to the Golgi complex to be added back to membranes in the Trans
Golgi region. This would recycle the receptor. This process is
similar to the process by which lysosomal
enzyme receptors are recycled. In many cases, the receptor is
sent back to the plasma membrane after a transport vesicle buds from
the endosome. This event is shown in the above photograph.
Willingham and Pastan used ferritin labeled antibodies to the
extracellular domain of the receptor to follow recycling
(transferrin receptor). This photograph was taken from
Endocytosis, Edited by Ira Pastan and Mark C. Willingham,
Plenum Press, N.Y., 1985
As stated in the above paragraphs, in cases where the receptor is
recycled from a budding endosome, the endosome itself is called an
"early endosome". In other words, the pH has dropped just enough to
allow the ligand to drop off, however, the receptor is not degraded.
This keeps it intact so it can be recycled back to the membrane.
Late endosomes are formed as the pH continues to drop to 5-6.0.
Also, clathrin-coated vesicles from the Trans Golgi Network carry
digestive enzymes to the late endosome and fuse with these structures,
releasing their contents. The late endosome thus becomes a degradative
body and also acquires the marker for mannose 6 phosphate receptor
"MPR+
It changes its rab surface marker to rab7-GTP, probably to accommodate
the new targeting vesicles with which it will fuse. This means that the
late endosome can be identified by the presence of the rab7.
Late endosomes include multivesicular bodies and contain whorls or
vesicles of membranes inside. They also contain an unusual lipid which has
become another marker for this stage. The lipid is called
lysobisphosphatidic acid (LBPA) which has a larger head group than tail.
Its structure enables it to be inserted into highly curved membranes, like
the membrane whorls. It is believed that this allows retention and
binding of specific molecules in the whorls by lipid-protein; lipid-lipid
interactions. One type of molecule is cholesterol and it is believed
that this is an important site for cholesterol accumulation.
For more information about the role of LBPA, see: Kobayashi, T,
Beuchat, M.H, Lindsay, M, Frias S, Palmiter, R.D., Sakuraba, H, Parton,
R.G, and Gruenberg, J. Late endosomal membranes rich in
lysobisphosphatidic acid regulate cholesterol transport. Nature Cell
Biology 1: 113-118.
Late endosomes function to degrade many proteins and lipids. They
also are responsible for returning the MPR receptors back to the Trans
Golgi network. They recycle these by budding off membranes that
carry back the receptors and target the Trans Golgi membranes for
fusion. After fusion, the MRP receptors are available to capture and
sort new degradative enzymes for future trafficking to the late
endosomes.
To summarize, markers for late endosomes include:
Late endosomes fuse with lysosomes.
Finally, late endosomes may not be able to digest all the material.
Therefore, the next step is a fusion of late endosomes and lysosomes
creating a hybrid organelle. Residual heavily glycosylated lysosomal
associated membrane proteins (LAMPs) may thus be transmitted to
lysosomes. LAMPs then become a marker for a late endosome or a
lysosome. Since lysosomes do not have MPR receptors (they have all been
sent to the Golgi), one could distinguish the lysosome and the late
endosome on the basis of labeling for MPR. Thus, fusion begins after
the MPR have been sent back to the Trans Golgi.
The steps involved in forming late endosomes and lysosomes are drawn in
this cartoon. Note that lysosomes continue to communicate with late
endosomes and may deliver important material back to this group of
organelles. Lysosomes are considered the end product of
endocytosis. Thus, lysosomes do not communicate directly with
the Trans Golgi (and hence the plasma membrane). However, they could
communicate with upstream structures by way of the retrograde transport to
the late endosome.
To summarize, markers for lysosomes include:
- LAMP+
- acid hydrolases
- MPR negative
- NPC1 (in normal
cells)
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