Editing Endosome

{{short description|Vacuole to which materials ingested by endocytosis are delivered}}
{{Redirect|Endosoma|Endosomaphilia|Vorarephilia}}
[[File:HeLa cell endocytic pathway labeled for EGFR and transferrin.jpg|thumb|315px|alt=endocytic pathway compartments|Electron micrograph of endosomes in human [[HeLa cell]]s. Early endosomes (E - labeled for EGFR, 5 minutes after internalisation, and transferrin), late endosomes/MVBs (M) and lysosomes (L) are visible. Bar, 500 nm.]]

'''Endosomes''' are a collection of intracellular sorting [[organelles]] in [[eukaryotic]] [[cell (biology)|cells]]. They are parts of the [[Endocytosis|endocytic]] membrane transport pathway originating from the [[trans Golgi network]]. Molecules or ligands internalized from the [[plasma membrane]] can follow this pathway all the way to [[lysosome]]s for degradation or can be recycled back to the [[cell membrane]] in the [[endocytic cycle]]. Molecules are also transported to endosomes from the trans Golgi network and either continue to lysosomes or recycle back to the [[Golgi apparatus]].

Endosomes can be classified as early, sorting, or late depending on their stage post internalization.<ref>{{cite journal | vauthors = Stoorvogel W, Strous GJ, Geuze HJ, Oorschot V, Schwartz AL | title = Late endosomes derive from early endosomes by maturation | journal = Cell | volume = 65 | issue = 3 | pages = 417–27 | date = May 1991 | pmid = 1850321 | doi = 10.1016/0092-8674(91)90459-C | s2cid = 31539542 }}</ref> Endosomes represent a major sorting compartment of the [[endomembrane system]] in cells.<ref name="endo1">{{cite journal | vauthors = Mellman I | title = Endocytosis and molecular sorting | journal = Annual Review of Cell and Developmental Biology | volume = 12 | pages = 575–625 | year = 1996 | pmid = 8970738 | doi = 10.1146/annurev.cellbio.12.1.575 }}</ref>

== Function ==
{{Further|Endocytic cycle}}
Endosomes provide an environment for material to be sorted before it reaches the degradative lysosome.<ref name="endo1" /> For example, [[low-density lipoprotein]] (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, [[epidermal growth factor]] (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 [[Ligand (biochemistry)|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''.<ref name="endo1" /> They are distinguished by the time it takes for endocytosed material to reach them, and by markers such as [[Rab (G-protein)|Rabs]].<ref name="Stenmark-2009">{{cite journal | vauthors = Stenmark H | title = Rab GTPases as coordinators of vesicle traffic | journal = Nature Reviews. Molecular Cell Biology | volume = 10 | issue = 8 | pages = 513–25 | date = August 2009 | pmid = 19603039 | doi = 10.1038/nrm2728 | s2cid = 33236823 }}</ref> They also have different morphology. Once [[Endocytosis|endocytic]] vesicles have uncoated, they fuse with early endosomes. Early endosomes then ''mature'' into late endosomes before fusing with lysosomes.<ref name="Futter-1996">{{cite journal | vauthors = Futter CE, Pearse A, Hewlett LJ, Hopkins CR | title = Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes | journal = The Journal of Cell Biology | volume = 132 | issue = 6 | pages = 1011–23 | date = March 1996 | pmid = 8601581 | pmc = 2120766 | doi = 10.1083/jcb.132.6.1011 }}</ref><ref name="eele2">{{cite journal | vauthors = Luzio JP, Rous BA, Bright NA, Pryor PR, Mullock BM, Piper RC | title = Lysosome-endosome fusion and lysosome biogenesis | journal = Journal of Cell Science | volume = 113 ( Pt 9) | pages = 1515–24 | date = May 2000 | issue = 9 | doi = 10.1242/jcs.113.9.1515 | pmid = 10751143 | doi-access = free }}</ref>

Early endosomes mature in several ways to form late endosomes. They become increasingly acidic mainly through the activity of the V-ATPase.<ref name="Lafourcade-2008">{{cite journal | vauthors = Lafourcade C, Sobo K, Kieffer-Jaquinod S, Garin J, van der Goot FG | title = Regulation of the V-ATPase along the endocytic pathway occurs through reversible subunit association and membrane localization | journal = PLOS ONE | volume = 3 | issue = 7 | pages = e2758 | date = July 2008 | pmid = 18648502 | pmc = 2447177 | doi = 10.1371/journal.pone.0002758 | editor1-last = Joly | editor1-first = Etienne | bibcode = 2008PLoSO...3.2758L | doi-access = free }}</ref> 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.<ref name="Rink-2005">{{cite journal | vauthors = Rink J, Ghigo E, Kalaidzidis Y, Zerial M | title = Rab conversion as a mechanism of progression from early to late endosomes | journal = Cell | volume = 122 | issue = 5 | pages = 735–49 | date = September 2005 | pmid = 16143105 | doi = 10.1016/j.cell.2005.06.043 | doi-access = free }}</ref> 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]]s and mannose 6-phosphate receptors continues during this period, probably via budding of vesicles out of endosomes.<ref name="Futter-1996" /> Finally, the endosomes lose [[RAB5A]] and acquire [[RAB7A]], making them competent for fusion with lysosomes.<ref name="Rink-2005" />

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.<ref name="endo-lysfus">{{cite journal | vauthors = Mullock BM, Bright NA, Fearon CW, Gray SR, Luzio JP | title = Fusion of lysosomes with late endosomes produces a hybrid organelle of intermediate density and is NSF dependent | journal = The Journal of Cell Biology | volume = 140 | issue = 3 | pages = 591–601 | date = February 1998 | pmid = 9456319 | pmc = 2140175 | doi = 10.1083/jcb.140.3.591 }}</ref> 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,<ref name="fastrecyc1">{{cite journal | vauthors = Hopkins CR, Trowbridge IS | title = Internalization and processing of transferrin and the transferrin receptor in human carcinoma A431 cells | journal = The Journal of Cell Biology | volume = 97 | issue = 2 | pages = 508–21 | date = August 1983 | pmid = 6309862 | pmc = 2112524 | doi = 10.1083/jcb.97.2.508 }}</ref> but most traffics via recycling endosomes.

*''Early endosomes'' consist of a dynamic tubular-vesicular network (vesicles up to 1&nbsp;μm in diameter with connected tubules of approx. 50&nbsp;nm diameter). Markers include [[RAB5A]] and RAB4, [[Transferrin]] and its [[Transferrin receptor|receptor]] 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.<ref name="Russell-2006">{{cite journal | vauthors = Russell MR, Nickerson DP, Odorizzi G | title = Molecular mechanisms of late endosome morphology, identity and sorting | journal = Current Opinion in Cell Biology | volume = 18 | issue = 4 | pages = 422–8 | date = August 2006 | pmid = 16781134 | doi = 10.1016/j.ceb.2006.06.002 }}</ref> In addition to this, the late endosomal membrane (and consequently the lysosome) contains a peculiar and unique [[lipid]] named BMP or LBPA, which is not found in any other organelle membrane.<ref>{{Cite journal |last1=Kobayashi |first1=Toshihide |last2=Beuchat |first2=Marie-Hélène |last3=Chevallier |first3=Julien |last4=Makino |first4=Asami |last5=Mayran |first5=Nathalie |last6=Escola |first6=Jean-Michel |last7=Lebrand |first7=Cecile |last8=Cosson |first8=Pierre |last9=Kobayashi |first9=Tetsuyuki |last10=Gruenberg |first10=Jean |date=2002-08-30 |title=Separation and characterization of late endosomal membrane domains |journal=The Journal of Biological Chemistry |volume=277 |issue=35 |pages=32157–32164 |doi=10.1074/jbc.M202838200 |issn=0021-9258 |pmid=12065580|doi-access=free }}</ref><ref name="Hullin-Matsuda 313–324">{{Cite journal |last1=Hullin-Matsuda |first1=F. |last2=Luquain-Costaz |first2=C. |last3=Bouvier |first3=J. |last4=Delton-Vandenbroucke |first4=I. |date=November 2009 |title=Bis(monoacylglycero)phosphate, a peculiar phospholipid to control the fate of cholesterol: Implications in pathology |url=https://pubmed.ncbi.nlm.nih.gov/19857945/ |journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids |volume=81 |issue=5–6 |pages=313–324 |doi=10.1016/j.plefa.2009.09.006 |issn=1532-2823 |pmid=19857945}}</ref>
*''Recycling endosomes'' are concentrated at the microtubule organizing center and consist of a mainly tubular network. Marker; RAB11.<ref name="Ullrich-1996">{{cite journal | vauthors = Ullrich O, Reinsch S, Urbé S, Zerial M, Parton RG | title = Rab11 regulates recycling through the pericentriolar recycling endosome | journal = The Journal of Cell Biology | volume = 135 | issue = 4 | pages = 913–24 | date = November 1996 | pmid = 8922376 | pmc = 2133374 | doi = 10.1083/jcb.135.4.913 }}</ref>

More subtypes exist in specialized cells such as polarized cells and [[macrophage]]s.

[[Phagosomes]], [[macropinosome]]s and [[autophagosome]]s<ref name="Fader-2009">{{cite journal | vauthors = Fader CM, Colombo MI | title = Autophagy and multivesicular bodies: two closely related partners | journal = Cell Death and Differentiation | volume = 16 | issue = 1 | pages = 70–8 | date = January 2009 | pmid = 19008921 | doi = 10.1038/cdd.2008.168 | doi-access = free }}</ref> 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.<ref name="Körner-2006">{{cite journal | vauthors = Körner U, Fuss V, Steigerwald J, Moll H | title = Biogenesis of Leishmania major-harboring vacuoles in murine dendritic cells | journal = Infection and Immunity | volume = 74 | issue = 2 | pages = 1305–12 | date = February 2006 | pmid = 16428780 | pmc = 1360340 | doi = 10.1128/IAI.74.2.1305-1312.2006 }}</ref>

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]] signaling molecules, is found to differ as the endosomes mature from early to late. [[Phosphatidylinositol 4,5-bisphosphate|PI(4,5)P<sub>2</sub>]] is present on [[Cell membrane|plasma membranes]], [[Phosphatidylinositol 3-phosphate|PI(3)P]] on early endosomes, PI(3,5)P<sub>2</sub> on late endosomes and [[Phosphatidylinositol 4-phosphate|PI(4)P]] on the [[trans Golgi network]].<ref>{{cite journal | vauthors = van Meer G, Voelker DR, Feigenson GW | title = Membrane lipids: where they are and how they behave | journal = Nature Reviews. Molecular Cell Biology | volume = 9 | issue = 2 | pages = 112–24 | date = February 2008 | pmid = 18216768 | pmc = 2642958 | doi = 10.1038/nrm2330 }}</ref> 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 [[kinase]]s and [[phosphatases]] that are strategically localized<ref>{{cite journal | vauthors = Di Paolo G, De Camilli P | title = Phosphoinositides in cell regulation and membrane dynamics | journal = Nature | volume = 443 | issue = 7112 | pages = 651–7 | date = October 2006 | pmid = 17035995 | doi = 10.1038/nature05185 | bibcode = 2006Natur.443..651D | s2cid = 4421550 }}</ref>

==Pathways==
[[File:Endocytic pathway of animal cells showing EGF receptors, transferrin receptors and mannose-6-phosphate receptors.jpg|thumb|315px|alt=animal cell endocytic pathway|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 [[epithelium|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 [[Exosome (vesicle)|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 [[GGA1|GGAs]] and [[AP1G1|AP-1]] [[clathrin-coated vesicle]] adaptors make vesicles at the Golgi that carry molecules to endosomes.<ref name="Ghosh-2004">{{cite journal | vauthors = Ghosh P, Kornfeld S | title = The GGA proteins: key players in protein sorting at the trans-Golgi network | journal = European Journal of Cell Biology | volume = 83 | issue = 6 | pages = 257–62 | date = July 2004 | pmid = 15511083 | doi = 10.1078/0171-9335-00374 }}</ref> In the opposite direction, [[retromer]] 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 [[Rab (G-protein)|Rab9]] and [[TIP47]], 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 [[endocytosis|endocytic]] vesicles. Molecules can be internalized via [[receptor-mediated endocytosis]] in [[clathrin]]-coated vesicles. Other types of vesicles also form at the plasma membrane for this pathway, including ones utilising [[caveolae|caveolin]]. Vesicles also transport molecules directly back to the plasma membrane, but many molecules are transported in vesicles that first fuse with recycling endosomes.<ref name="Grant-2009">{{cite journal | vauthors = Grant BD, Donaldson JG | title = Pathways and mechanisms of endocytic recycling | journal = Nature Reviews. Molecular Cell Biology | volume = 10 | issue = 9 | pages = 597–608 | date = September 2009 | pmid = 19696797 | pmc = 3038567 | doi = 10.1038/nrm2755 }}</ref> Molecules following this recycling pathway are concentrated in the tubules of early endosomes. Molecules that follow these pathways include the [[Receptor (biochemistry)|receptors]] for [[LDL]], [[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]] 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]] (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<ref name="Futter-2001">{{cite journal | vauthors = Futter CE, Collinson LM, Backer JM, Hopkins CR | title = Human VPS34 is required for internal vesicle formation within multivesicular endosomes | journal = The Journal of Cell Biology | volume = 155 | issue = 7 | pages = 1251–64 | date = December 2001 | pmid = 11756475 | pmc = 2199316 | doi = 10.1083/jcb.200108152 }}</ref> - in cells not stimulated with EGF, EGFRs have no EGF bound to them and therefore recycle if they reach endosomes.<ref name="Felder-1990">{{cite journal | vauthors = Felder S, Miller K, Moehren G, Ullrich A, Schlessinger J, Hopkins CR | title = Kinase activity controls the sorting of the epidermal growth factor receptor within the multivesicular body | journal = Cell | volume = 61 | issue = 4 | pages = 623–34 | date = May 1990 | pmid = 2344614 | doi = 10.1016/0092-8674(90)90474-S | s2cid = 22770514 }}</ref> 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.<ref name="Dautry-Varsat-1986">{{cite journal | vauthors = Dautry-Varsat A | title = Receptor-mediated endocytosis: the intracellular journey of transferrin and its receptor | journal = Biochimie | volume = 68 | issue = 3 | pages = 375–81 | date = March 1986 | pmid = 2874839 | doi = 10.1016/S0300-9084(86)80004-9 }}</ref>

===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<ref name="pmid34611326">{{cite journal | vauthors = Jackson CB, Farzan M, Chen B, Choe H | title = Mechanisms of SARS-CoV-2 entry into cells | journal = [[Nature Reviews Molecular Cell Biology]] | volume = 23 | issue=1 | pages = 3–20 | date = 2022 | doi = 10.1038/s41580-021-00418-x | pmc = 8491763 | pmid = 34611326}}</ref><ref name="pmid33324224">{{cite journal | vauthors = Khan N, Chen X, Geiger JD | title = Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments | journal = [[Frontiers in Pharmacology]] | volume = 11 | pages = 595888 | date = 2020 | doi = 10.3389/fphar.2020.595888 | pmc = 7723437 | pmid = 33324224| doi-access = free }}</ref>). Hence, soluble molecules in the lumen of endosomes will tend to end up in lysosomes, unless they are retrieved in some way. [[Transmembrane protein]]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.<ref name="Hullin-Matsuda 313–324"/> 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]].<ref name="Hicke-2003">{{cite journal | vauthors = Hicke L, Dunn R | title = Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins | journal = Annual Review of Cell and Developmental Biology | volume = 19 | pages = 141–72 | year = 2003 | pmid = 14570567 | doi = 10.1146/annurev.cellbio.19.110701.154617 }}</ref> The [[endosomal sorting complexes required for transport]] (ESCRTs) recognise this ubiquitin and sort the protein into the forming lumenal vesicles.<ref name="Hurley-2008">{{cite journal | vauthors = Hurley JH | title = ESCRT complexes and the biogenesis of multivesicular bodies | journal = Current Opinion in Cell Biology | volume = 20 | issue = 1 | pages = 4–11 | date = February 2008 | pmid = 18222686 | pmc = 2282067 | doi = 10.1016/j.ceb.2007.12.002 }}</ref> 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 (vesicle)|Exosome]]
*[[Paramural body]]

== References ==
{{reflist|30em}}
* {{cite book |last=Alberts |first=Bruce |title=Essential Cell Biology |url=https://archive.org/details/essentialcellbio00albe |edition=2nd |year=2004 |publisher=Garland Science |location=New York, NY |isbn=978-0-8153-3480-4 |display-authors=etal |url-access=registration }}

== External links ==
*[http://opm.phar.umich.edu/localization.php?localization=Endosome%20membrane 3D structures of some proteins associated with endosome membrane]

{{Organelles}}

[[Category:Vesicles]]
[[Category:Organelles]]