![HeLa cell endocytic pathway labeled for EGFR and transferrin](https://upload.wikimedia.org/wikipedia/commons/8/85/HeLa_cell_endocytic_pathway_labeled_for_EGFR_and_transferrin.jpg)
Endosomes are a collection of intracellular sorting
organelles
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...
in
eukaryotic
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
cells. They are parts of
endocytic membrane transport pathway originating from the
trans Golgi network
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
. Molecules or ligands internalized from the
plasma membrane can follow this pathway all the way to
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...
s for degradation or can be recycled back to the
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
in the
endocytic cycle
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. ...
. Molecules are also transported to endosomes from the trans Golgi network and either continue to lysosomes or recycle back to the
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ...
.
Endosomes can be classified as early, sorting, or late depending on their stage post internalization. Endosomes represent a major sorting compartment of the
endomembrane system
The endomembrane system is composed of the different membranes (endomembranes) that are suspended in the cytoplasm within a eukaryotic cell. These membranes divide the cell into functional and structural compartments, or organelles. In eukaryotes ...
in cells.
Function
Endosomes provide an environment for material to be sorted before it reaches the degradative lysosome.
For example,
low-density lipoprotein
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall dens ...
(LDL) is taken into the cell by binding to the
LDL receptor
The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor ...
at the cell surface. Upon reaching early endosomes, the LDL dissociates from the receptor, and the receptor can be recycled to the cell surface. The LDL remains in the endosome and is delivered to lysosomes for processing. LDL dissociates because of the slightly acidified environment of the early endosome, generated by a vacuolar membrane proton pump
V-ATPase
Vacuolar-type ATPase (V-ATPase) is a highly conserved evolutionarily ancient enzyme with remarkably diverse functions in eukaryotic organisms. V-ATPases acidify a wide array of intracellular organelles and pumps protons across the plasm ...
. On the other hand, EGF and the EGF receptor have a pH-resistant bond that persists until it is delivered to lysosomes for their degradation. The
mannose 6-phosphate receptor carries
ligands from the Golgi destined for the lysosome by a similar mechanism.
Types
There are three different types of endosomes: ''early endosomes'', ''late endosomes'', and ''recycling endosomes''.
They are distinguished by the time it takes for endocytosed material to reach them, and by markers such as
rabs.
They also have different morphology. Once
endocytic vesicles have uncoated, they fuse with early endosomes. Early endosomes then ''mature'' into late endosomes before fusing with lysosomes.
Early endosomes mature in several ways to form late endosomes. They become increasingly acidic mainly through the activity of the V-ATPase.
Many molecules that are recycled are removed by concentration in the tubular regions of early endosomes. Loss of these tubules to recycling pathways means that late endosomes mostly lack tubules. They also increase in size due to the homotypic fusion of early endosomes into larger vesicles.
Molecules are also sorted into smaller vesicles that bud from the perimeter membrane into the endosome lumen, forming intraluminal vesicles (ILVs); this leads to the multivesicular appearance of late endosomes and so they are also known as multivesicular endosomes or multivesicular bodies (MVBs). Removal of recycling molecules such as
transferrin receptor
Transferrin receptor (TfR) is a carrier protein
A membrane transport protein (or simply transporter) is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membr ...
s and mannose 6-phosphate receptors continues during this period, probably via budding of vesicles out of endosomes.
Finally, the endosomes lose
RAB5A
Ras-related protein Rab-5A is a protein that in humans is encoded by the ''RAB5A'' gene.
Function
RAB5A localizes to early endosomes where it is involved in the recruitment of RAB7A and the maturation of these compartments to late endosomes. I ...
and acquire
RAB7A
Ras-related protein Rab-7a is a protein that in humans is encoded by the ''RAB7A'' gene.
Ras-related protein Rab-7a is involved in endocytosis, which is a process that brings substances into a cell. The process of endocytosis works by folding the ...
, making them competent for fusion with lysosomes.
Fusion of late endosomes with lysosomes has been shown to result in the formation of a 'hybrid' compartment, with characteristics intermediate of the two source compartments.
For example, lysosomes are more dense than late endosomes, and the hybrids have an intermediate density. Lysosomes reform by recondensation to their normal, higher density. However, before this happens, more late endosomes may fuse with the hybrid.
Some material recycles to the plasma membrane directly from early endosomes,
but most traffics via recycling endosomes.
*''Early endosomes'' consist of a dynamic tubular-vesicular network (vesicles up to 1 µm in diameter with connected tubules of approx. 50 nm diameter). Markers include
RAB5A
Ras-related protein Rab-5A is a protein that in humans is encoded by the ''RAB5A'' gene.
Function
RAB5A localizes to early endosomes where it is involved in the recruitment of RAB7A and the maturation of these compartments to late endosomes. I ...
and RAB4,
Transferrin
Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encode ...
and its
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
and
EEA1.
*''Late endosomes'', also known as MVBs, are mainly spherical, lack tubules, and contain many close-packed intraluminal vesicles. Markers include RAB7, RAB9, and mannose 6-phosphate receptors.
In addition to this, the late endosomal membrane (and consequently the lysosome) contains a peculiar and unique
Lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
, named BMP or LBPA, which is not found in any other eukaryotic cell membrane.
*''Recycling endosomes'' are concentrated at the microtubule organizing center and consist of a mainly tubular network. Marker; RAB11.
More subtypes exist in specialized cells such as polarized cells and
macrophages.
Phagosomes
In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).
A phagosome is formed by the fusion of the cell me ...
,
macropinosome
Macropinosomes are a type of cellular compartment that form as a result of macropinocytosis.
Formation
Macropinosomes have been described to form via a wave-like mechanism or via a tent-pole formation both of which processes require rapid polyme ...
s and
autophagosome
An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles, i ...
s
mature in a manner similar to endosomes, and may require fusion with normal endosomes for their maturation. Some intracellular pathogens subvert this process, for example, by preventing RAB7 acquisition.
Late endosomes/MVBs are sometimes called ''endocytic carrier vesicles'', but this term was used to describe vesicles that bud from early endosomes and fuse with late endosomes. However, several observations (described above) have now demonstrated that it is more likely that transport between these two compartments occurs by a maturation process, rather than vesicle transport.
Another unique identifying feature that differs between the various classes of endosomes is the lipid composition in their membranes. Phosphatidyl inositol phosphates (PIPs), one of the most important
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
signaling molecules, is found to differ as the endosomes mature from early to late.
PI(4,5)P2 is present on
plasma membranes
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
,
PI(3)P on early endosomes, PI(3,5)P
2 on late endosomes and
PI(4)P on the
trans Golgi network
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
. These lipids on the surface of the endosomes help in the specific recruitment of proteins from the cytosol, thus providing them an identity. The inter-conversion of these lipids is a result of the concerted action of phosphoinositide
kinases and
phosphatases
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. ...
that are strategically localized
Pathways
There are three main compartments that have pathways that connect with endosomes. More pathways exist in specialized cells, such as
melanocytes and polarized cells. For example, in
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
cells, a special process called
transcytosis Transcytosis (also known as cytopempsis) is a type of transcellular transport in which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ...
allows some materials to enter one side of a cell and exit from the opposite side. Also, in some circumstances, late endosomes/MVBs fuse with the plasma membrane instead of with lysosomes, releasing the lumenal vesicles, now called
exosomes, into the extracellular medium.
There is no consensus as to the exact nature of these pathways, and the sequential route taken by any given cargo in any given situation will tend to be a matter of debate.
Golgi to/from endosomes
Vesicles pass between the Golgi and endosomes in both directions. The
GGAs and
AP-1 clathrin-coated vesicle adaptors make vesicles at the Golgi that carry molecules to endosomes.
In the opposite direction,
retromer Retromer is a complex of proteins that has been shown to be important in recycling transmembrane receptors from endosomes to the ''trans''-Golgi network (TGN).
Background
Retromer is a heteropentameric complex, which in humans is composed of a ...
generates vesicles at early endosomes that carry molecules back to the Golgi. Some studies describe a retrograde traffic pathway from late endosomes to the Golgi that is mediated by
Rab9 and
TIP47
Mannose-6-phosphate receptor binding protein 1 (M6PRBP1) is a protein which in humans is encoded by the ''M6PRBP1'' gene. Its gene product, as well as the gene itself, is commonly known as TIP47.
Function
Mannose 6-phosphate receptors (MPRs) ...
, but other studies dispute these findings. Molecules that follow these pathways include the mannose-6-phosphate receptors that carry lysosomal hydrolases to the endocytic pathway. The hydrolases are released in the acidic environment of endosomes, and the receptor is retrieved to the Golgi by retromer and Rab9.
Plasma membrane to/from early endosomes (via recycling endosomes)
Molecules are delivered from the plasma membrane to early endosomes in
endocytic vesicles. Molecules can be internalized via
receptor-mediated endocytosis in
clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When ...
-coated vesicles. Other types of vesicles also form at the plasma membrane for this pathway, including ones utilising
caveolin. Vesicles also transport molecules directly back to the plasma membrane, but many molecules are transported in vesicles that first fuse with recycling endosomes.
Molecules following this recycling pathway are concentrated in the tubules of early endosomes. Molecules that follow these pathways include the
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
for
LDL
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
,
epidermal growth factor (EGF), and the iron transport protein transferrin. Internalization of these receptors from the plasma membrane occurs by receptor-mediated endocytosis. LDL is released in endosomes because of the lower pH, and the receptor is recycled to the cell surface.
Cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
is carried in the blood primarily by (LDL), and transport by the LDL receptor is the main mechanism by which cholesterol is taken up by cells. EGFRs are activated when EGF binds. The activated receptors stimulate their own internalization and degradation in lysosomes. EGF remains bound to the
EGF receptor EGF may refer to:
* E.G.F., a Gabonese company
* East Grand Forks, Minnesota, a city
* East Garforth railway station in England
* Epidermal growth factor
* Equity Group Foundation, a Kenyan charity
* European Gendarmerie Force, a military unit o ...
(EGFR) once it is endocytosed to endosomes. The activated EGFRs stimulate their own ubiquitination, and this directs them to lumenal vesicles (see below) and so they are not recycled to the plasma membrane. This removes the signaling portion of the protein from the cytosol and thus prevents continued stimulation of growth
- in cells not stimulated with EGF, EGFRs have no EGF bound to them and therefore recycle if they reach endosomes.
Transferrin also remains associated with its receptor, but, in the acidic endosome, iron is released from the transferrin, and then the iron-free transferrin (still bound to the transferrin receptor) returns from the early endosome to the cell surface, both directly and via recycling endosomes.
Late endosomes to lysosomes
Transport from late endosomes to lysosomes is, in essence, unidirectional, since a late endosome is "consumed" in the process of fusing with a lysosome (sometimes called endolysosome
).Hence, soluble molecules in the lumen of endosomes will tend to end up in lysosomes, unless they are retrieved in some way.
Transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
s can be delivered to the perimeter membrane or the lumen of lysosomes. Transmembrane proteins destined for the lysosome lumen are sorted into the vesicles that bud from the perimeter membrane into endosomes, a process that begins in early endosomes. The process of creating vesicles within the endosome is thought to be enhanced by the peculiar lipid BMP or LBPA, which is only found in late endosomes, endolysosomes or lysosomes.
When the endosome has matured into a late endosome/MVB and fuses with a lysosome, the vesicles in the lumen are delivered to the lysosome lumen. Proteins are marked for this pathway by the addition of
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
.
The
endosomal sorting complexes required for transport (ESCRTs) recognise this ubiquitin and sort the protein into the forming lumenal vesicles.
Molecules that follow these pathways include LDL and the lysosomal hydrolases delivered by mannose-6-phosphate receptors. These soluble molecules remain in endosomes and are therefore delivered to lysosomes. Also, the transmembrane EGFRs, bound to EGF, are tagged with ubiquitin and are therefore sorted into lumenal vesicles by the ESCRTs.
See also
*
Back-Fusion
*
Exosome
*
Paramural body
References
*
External links
3D structures of some proteins associated with endosome membrane
{{Organelles
Vesicles
Organelles