User:Langmath/sandbox/Endosome-associated recycling protein (EARP)

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In cell biology, an endosome-associated recycling protein complex (EARP) is involved in salvaging molecules from vesicles headed to degradation in lysosomes back to the endocytic/secretory pathway. Optimally, the transgolgi creates waves of vesicles (early endosomes) that serve as staging areas, or as a central hub to mediate cargos from and between 3 organelles: golgi, lysosome, cell membrane. The utility in this process is to prevent contamination, notably from endocytosis, by keeping these organelles physically distinct. As long as endocytized foreign material is within the lumen of vesicles, and not the golgi, it can be easily sent to the lysosome without needing to identify and sort every dangerous particle. Similarly, golgi-associated retrograde protein complex (GARP) salvages molecules headed to degradation in lysosomes back to the golgi. The difference in naming convention (recycling vs retrograde) reflects the directionality in GARP in contrast to the purpose in EARP. Recycling endosomes are a crucial area of research. The function of EARP is the difference between cell surface receptor fates after increased activity, leading to upregulation (recycled after overuse) or downregulation (lysosome after overuse). This has major implications for long-term potentiation (LTP) in neurons, endocrine signaling throughout the body, as well as generic cell health.

Function

Endosomes provide an environment for material to be sorted before it reaches the degradative lysosome. For example,

LDL is taken into the cell by binding to the LDL 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. 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

Endosomes comprise three different compartments: 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 lumenal vesicles; this leads to the multivesicular appearance of late endosomes and so they are also known as multivesicular bodies (MVBs). Removal of recycling molecules such as transferrin receptors and mannose 6-phosphate receptors continues during this period, probably via budding of vesicles out of endosomes. Finally, the endosomes lose RAB5A and acquire RAB7A, 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 and RAB4, Transferrin and its receptor and EEA1.
Late endosomes, also known as MVBs, are mainly spherical, lack tubules, and contain many close-packed lumenal vesicles. Markers include RAB7, RAB9, and mannose 6-phosphate receptors.

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.

autophagosomes

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. Phosphotidyl inositol phosphates (PIPs), one of the most important

phosphatases

that are strategically localized

Pathways

Diagram of the pathways that intersect endosomes in the endocytic pathway of animal cells. Examples of molecules that follow some of the pathways are shown, including receptors for EGF, transferrin, and lysosomal hydrolases. Recycling endosomes, and compartments and pathways found in more specialized cells, are not shown.

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 cells, a special process called transcytosis 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.

It should be noted that 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.