Editing Endosome (section)

==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.