Abstract
SummaryMembrane contact sites between the ER and multivesicular endosomes/bodies (MVBs) play important roles in endosome positioning and fission and in neurite outgrowth. ER-MVB contacts additionally function in epidermal growth factor receptor (EGFR) tyrosine kinase downregulation by providing sites where the ER-localized phosphatase, PTP1B, interacts with endocytosed EGFR before the receptor is sorted onto intraluminal vesicles (ILVs). Here we show that these contacts are tethered by annexin A1 and its Ca2+-dependent ligand, S100A11, and form a subpopulation of differentially regulated contact sites between the ER and endocytic organelles. Annexin A1-regulated contacts function in the transfer of ER-derived cholesterol to the MVB when low-density lipoprotein-cholesterol in endosomes is low. This sterol traffic depends on interaction between ER-localized VAP and endosomal oxysterol-binding protein ORP1L, and is required for the formation of ILVs within the MVB and thus for the spatial regulation of EGFR signaling.
Highlights
The ER forms an extensive network of membrane contact sites (MCSs), microdomains of close membrane apposition (
MCSs with a given multivesicular endosomes/bodies (MVBs) may not be in the plane of a random section, we found MCS quantification in random sections to be comparable with that achieved by serial sectioning (Figure S1A)
Focusing first on the potential role of the Vesicle-associated membrane protein-associated proteins (VAPs)-ORP1L interaction, we found that ER contacts with epidermal growth factor receptor (EGFR)-MVBs were unaffected by VAP depletion, but MCSs with non-EGFR-MVBs and lysosomes were reduced by approximately 50% (Figures 1B and S1B)
Summary
The ER forms an extensive network of membrane contact sites (MCSs), microdomains of close membrane apposition (
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