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Review
. 2015 Jul 14;34(14):1848-58.
doi: 10.15252/embj.201591481. Epub 2015 Jun 3.

ER-endosome contact sites: molecular compositions and functions

Camilla Raiborg  1 , Eva M Wenzel  1 , Harald Stenmark  2
Affiliations
Review

ER-endosome contact sites: molecular compositions and functions

Camilla Raiborg et al. EMBO J. .

Abstract

Recent studies have revealed the existence of numerous contact sites between the endoplasmic reticulum (ER) and endosomes in mammalian cells. Such contacts increase during endosome maturation and play key roles in cholesterol transfer, endosome positioning, receptor dephosphorylation, and endosome fission. At least 7 distinct contact sites between the ER and endosomes have been identified to date, which have diverse molecular compositions. Common to these contact sites is that they impose a close apposition between the ER and endosome membranes, which excludes membrane fusion while allowing the flow of molecular signals between the two membranes, in the form of enzymatic modifications, or ion, lipid, or protein transfer. Thus, ER-endosome contact sites ensure coordination of molecular activities between the two compartments while keeping their general compositions intact. Here, we review the molecular architectures and cellular functions of known ER-endosome contact sites and discuss their implications for human health.

Keywords: endoplasmic reticulum; endosome; membrane contact sites.

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Figures

Figure 1
Figure 1
Endosomes make contact with the endoplasmic reticulum (Left) Endosomes associate with tubular regions of the ER. (Right) Confocal micrograph showing how LEs (red) are juxtaposed to protrudin-positive ER (blue).
Figure 2
Figure 2
Organelles establish contact sites with a variety of cellular compartments In mammalian cells, ER makes contact sites with endosomes, Golgi, mitochondria, lipid droplets, and the plasma membrane. Lysosomes and peroxisomes also establish contact sites. Examples of proteins known to mediate the contact sites in metazoans are depicted (Helle et al, ; Rowland et al, ; Chu et al, ; Raiborg et al, 2015).
Figure 3
Figure 3
Cholesterol transfer in ER–endosome contact sites (A) Prior to contact formation, cholesterol-binding protein complexes define cholesterol-rich patches on the endosome membrane. Cholesterol, internalized into endosomes via LDL particles, is transferred to the cholesterol transporter NPC1 via the carrier NPC2. (B) Cholesterol accumulates in NPC1. Upon reduction in free cholesterol in the endosome membrane, ORP1L undergoes a conformational change which initiates binding to the ER protein VAP. The MENTAL domain of STARD3/NL can also bind to VAP in the ER. (C) The ER–endosome contact initiated by ORP1L-VAP-A might facilitate the interaction of ORP5 with NPC1. (D) When contact is established, cholesterol is transferred from the endosome to the ER via ORP5 and possibly also via the START domain of STARD3.
Figure 4
Figure 4
ER–endosome contacts regulate microtubule-dependent endosome transport (A) Prior to contact formation, under cholesterol-rich conditions, ORP1L-RILP is bound to the minus-end-directed microtubule motor dynein and the HOPS complex. This facilitates transport of endosomes to the cell centre where they can fuse in a HOPS-dependent manner. (B) When cholesterol levels are reduced, ORP1L undergoes a conformational change that initiates binding to the ER protein VAP-A. VAP-A dissociates dynein and HOPS from RILP. The ER protein protrudin is also localized to VAP-A sites of the ER membrane, where it concentrates the plus-end-directed microtubule motor kinesin-1. (C) Protrudin initiates contact with endosomes by binding to Rab7-GTP and PtdIns3P. The endosomal motor adaptor FYCO1 receives kinesin-1 from protrudin. (D) Endosomes are transported to the cell periphery by kinesin-1 coupled to FYCO1.
Figure 5
Figure 5
Dephosphorylation of endosomal receptors by an ER-associated phosphatase The ER-localized phosphatase PTP1B dephosphorylates activated EGFRs in the endosomal membrane. The ER–endosome association is likely to be stabilized by additional factors.
Figure 6
Figure 6
ER tubules define sites of endosome fission (A) EEs contain internalized EGF receptors (EGFRs) and transferrin receptors (TfRs). TfRs accumulate in forming endosome tubules, whereas EGFRs are retained in the endosome body. (B) The retromer-associated protein FAM-21 localizes to the base of a forming tubule, which is contacted by a tubular ER element that defines the site of constriction. (C) The endosomal TfR containing endosomal tubule is constricted as ER folds around it. (D) Constriction is followed by fission into a Rab5-positive endosome that contains EGFR and a Rab4-positive endosome that contains TfR.
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