The receptor recycling pathway



In brief, endosomes are post-Golgi eukaryotic organelles that are involved in the transport and distribution of proteins in cells. They have the capability to both give and receive proteins, and constitute a "junction" between the Golgi body, lysosomes and the plasma membrane of a cell, transporting proteins back and forth between all of the parties involved. This means they compose part of both the biosynthetic and endosytic pathways.

It is widely regarded that there are four types of endosomes: early endosomes, intermediate endosomes, late endosomes and recycling endosomes. The critical factor which determines the type of endosome is the amount of time that it takes for them to be reached by material which has entered the cell by endocytosis. The physical, biochemical and pharmological[i] differences between these types, especially in eukaryotic cells, is not always distinguishable In this review I will define and explain the structure and function of each of these four types of endosomes, and the pathways in which they are critical.

The Endocytic Pathway

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The endocytic pathway is a series of mechanisms by which entities can enter a cell. There a three distinct types of endocytosis as well as five key components. The principle components are early endosomes, indermediate endosomes, recycling endosomes, late endosomes and lysosomes. As the pathway progresses it becomes more acidic.iv

The first type of endocytosis is phagocytosis, which translated literally means "cell-eating". It involves the membrane of the cell forming a pocket to engulf and ingest large objects such as bacteria, viruses or organelles. It is understood that phagocytosis occurs sporadically and only in certain specialised cells. The second type of endocytosis is pinocytosis. This is a similar mechanism to phagocytosis, however involves the injestion of solutes rather than solids.

The final mechanism of the endocytic pathway is receptor-mediated endocytosis. The primary goal of this method is to uptake specific proteins by creating a pocket in the membrane which is lined with specific receptors. These receptors bind to the wanted protein using the "lock and key" mechanism, and intake the protein. This method reduces the amount of other unwanted substances endocytosised by the cell. A further and more detailed description of endocytosis can be found in "Mechanisms and functions of endocytosis" by M. Miaczynska and H. Stenmark[ii].

I will now outline the function and structure of the four known types of endosome.

The Four Types - Early

As the name suggests, early endosomes are the first type of endosomes to receive endocytosed matter. They are small and irregularly shaped intracellular organelle with a tubule-vesicular and cisternal morphology[iii] and an internal pH of between 5.9 and 6.0[iv]. They are characterised by the presence of the enzymes rab4, rab5 and transferrin receptor[v] (a transferrin carrier protein, vital for iron transport).

In mammals one of the principle functions of early endosomes is to accept secretory vesicles from the Golgi apparatus, part of exocytosis, and to fuse with vesicles from the plasma membrane, part of endocytosis. Furthermore early endosomes, along with recycling endosomes, are important in the recycling of plasma membrane proteins[vi], believed to be aided by the protein Syntaxin 13[vii]. A study by Rytis Prekeris et al. showed, through confocal immunofluorescence and electron microscopy, that Syntaxin 13 is "primarily found in tubular early and recycling endosomes, where it colocalizes with transferrin receptor" [Rytis Prekeris et al., 1998].

Once materials have undergone endocytosis and have entered the early endosomes they move to the intermediate and late endosomes. Early endosomes travel along microtubules towards the middle of the cell. As this happens the early endosomal membrane folds and forms vesicles, which are shed. At this point the endosome becomes a multivesicular body (MVB). In developing seeds they act as prevacuolar compartments, carrying storage proteins and processing proteases and deposit them in protein storage vacuoles.

Generally speaking, fusion occurs between the MVBs and either the late endosomal compartment or each other. This forms late endosomes.

The Four Types - Intermediate & Late

Late endosomes are the site of hydrolytic digestion of endocytosed material. In order to aid this, the interior of these endosomes is slightly acidic. Late endosomes are the final step in the formation of mature lysosomes, which form following a maturation process.

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This is a key step in endocytosis. Late endosomes, however, are also involved in a secondary pathway in a cell types; autophagy. This involves the fusion of a double membrane of unknown origin, and a late endosome (or lysosome).

The principle role of intermediate and late endosomes is to direct and transfer proteins into internal vesicles[viii]. However, intermediate endosomes also act to recycle reserve vesicles, according to Gary Matthews in "Cycling the Synapse: Scenic versus Direct Routes for Vesicles", 2004.

The Four Types - Recycling & the Transcytotic pathway

A further key mechanism of endocytosis is transcytosis. This involves the transfer of specific macromolecules from "one extracellular space to another... by receptors on the surface of polarized epithelial cells" (Alberts et al, 2008). Endocytosis transfers the receptors into the cell's endosomes and then on a into a plasma membrane domain, however this is not direct. Firstly the receptors are moved from the early to recycling endosomes. Recycling endosomes can then dictate how much of each specific receptor/protein is allowed to leave it, allowing for regulation. This means that cells can adapt the number of proteins moving around the cell body, according to how much of each is required.

There has been a reasonable amount of research done into the various differences between early and recycling endosomes, largely because of there being some similarity in function. A research paper by D. R. Sheff et al. in 1999 titled "The Receptor Recycling Pathway Contains Two Distinct Populations of Early Endosomes with Different Sorting Functions" details three lines of evidence which aim to prove there are many differences between early and recycling endosomes. The three lines are physical (determined by centrifugation), biochemical (determined by protein composition), and pharmacologically (by differential sensitivity to AIF4)[ix].

External Threats of Infection

The position of endosomes in the cell, as well as their primary role and function, makes them open to attack and exploitation by viruses and bacteria. Certain viruses and bactera have developed mechanisms by which they can be taken into a cell by endocytosis, leaving the cell open to attackviii. An example of this is the bacterium Bacillus anthracis which causes the disease Anthrax. On the cell surface the bacterium binds to PA83 which then binds to an enzymatic subunit, either EF or LF, becoming PA63. It is taken through the cell membrane by Clathrin-mediated endocytosis and transported to the early endosomes. There are then several sorting steps in the MVBs following by a fusion event in which the toxins are released into the cytoplasm[x]. The bacterium utilises the low and progressively decreasing pH in the endosomes in a number of ways, including membrane insertion, channel formation and partial protein unfoldingx.

The Vesicular stomatitis virus (VSV), of the same family as the commonly known Rabies virus, also exploits the endocytic techniques of the cell. It attaches to the exterior of the target cell by the mediation of an appropriate glycoprotein which entirely surrounds the virus[xi]. Virus and glycoprotein are then engulfed by endocytosis and enters the endocytic pathway. As previously stated the pH of the endocytic pathway decreases as it reaches later stages, and it is this acidification that causes the change in shape of the glycoprotein. The glycoprotein is then shed in a process which allows the VSV to pass into the cytoplasm for replication.

It is interesting to note that endosomes can also be used by certain viruses to exit the cell[xii] (by exocytosis). For example, the HIV virus has the ability to bud into MVEs in macrophages and remain infectious[xiii]. Once "hidden" inside the late endosomes of a cell the virus would not be at risk from the immune system of the organism. This may mean that virus can remain virulent within the cell for a large amount of time, resulting in the prolonged infection of patients carrying the HIV virus[xiv].

Despite the fact that endosomal infection by bacteria or viruses can have catastrophic effects, it can also act as a beneficial mechanism. If a microorganism is taken in to the early endosomes by endocytosis and/or recognised then this is likely to trigger an autoimmune response by the cell; endosomes have a critical role in fighting infection.

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Pathogens can be sensed by mammalian cells through the use of TLRs 1-12 (toll-like receptors). When they detect viruses or bacteria they have the ability to trigger a response and the cell can fight off the infection.

Phagosomes are the vacuoles formed around large objects to be absorbed by phagocytosis, a form of endocytosis. They are formed out of folding in the cell membrane and their primary aim is to engulf proteins. Although newly formed phagosomes are unable to destroy microorganisms, once mature they are capable of doing so. At this stage they are called phagolysosomes, and are characterised by a highly acidic interior as well as an active NADPH oxidase complex, both of which are vital to microbial digestion.[xv]


I have discussed the various types and roles of endosomes and some of the pathways in which they play a critical part. There has been a great deal of research done into the nature of the structure and function of endosomes, and yet still much more that is yet to be found. With the extensive use of new technologies this research could particularly prove useful in the future for creating vectors for immunisationxi as well as better understanding how and why certain viral, bacterial and pathogenic diseases affect humans. For example, if the exact mechanism that the HIV virus uses to infect a host can be determined and studied in detail then it may be possible to counter its affects.

  1. "The Receptor Recycling Pathway Contains Two Distinct Populations of Early Endosomes with Different Sorting Functions"
  2. Marta Miaczynska and Harald Stenmark, J Cell Biol. 2008 January 14; 180 7-11
  3. Gruenberg & Howell 1989, Hopkins 1983, Griffiths et al. 1988, 1990
  4. Mellman et al. 1986, Yamashiro et al. 1984
  5. Griffiths et al. 1993, Chavrier et al. 1990, van der Sluijs et al. 1991, Ludvig et al. 1991, Lombardi et al. 1993, Ullrich et al. 1996
  6. Gruenberg and Stenmark. 2004. The biogenesis of multivesicular bodies. Nature Rev. Mol. Cell Biol., 5: 317-323.
  7. Rytis Prekeris et al., 1998 Syntaxin 13 Mediates Cycling of Plasma Membrane Proteins via Tubulovesicular Recycling Endosomes.
  8. Jean Gruenberg* and F. Gisou van der Goot, 2006/ Nature Volume 7, July 2006 495. "Mechanisms of pathogen entry through the endosomal compartments".
  9. "The Receptor Recycling Pathway Contains Two Distinct Populations of Early Endosomes with Different Sorting Functions"
  10. "Anthrax toxin: the long and winding road that leads to the kill" Laurence Abrami et al., TRENDS in Microbiology Vol.13 No.2 February 2005 72.
  11. B. D. Lichty et al., 2004. TRENDS in Molecular Medicine Vol.10 No.5 May 2004Vesicular stomatitis virus: re-inventing the bullet
  12. Infectious HIV-1 assembles in late endosomes in primary macrophages Annegret Pelchen-Matthews et al., J Cell Biol. 2003 August 4; 162(3): 443-455.
  13. Infectious HIV-1 assembles in late endosomes in primary macrophages Annegret Pelchen-Matthews et al., J Cell Biol. 2003 August 4; 162(3): 443-455.
  14. Infectious HIV-1 assembles in late endosomes in primary macrophages Annegret Pelchen-Matthews et al., J Cell Biol. 2003 August 4; 162(3): 443-455.
  15. Phagocytosis: at the crossroads of innate and adaptive immunity. Jutras, I. & Desjardins Rev. Cell Dev. Biol. 21, 511-527 (2005).