Annexin A1 Tethers Membrane Contact Sites that Mediate ER to Endosome Cholesterol Transport.
Membrane 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 Ca(2+)-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.
UCL Institute of Ophthalmology, London EC1V 9EL, UK.
Emily R
ER
Eden
UCL Institute of Ophthalmology, London EC1V 9EL, UK.
Elena
E
Sanchez-Heras
UCL Institute of Ophthalmology, London EC1V 9EL, UK; Technical University of Crete, 73100 Chania, Greece.
Anna
A
Tsapara
Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland.
Andrzej
A
Sobota
UCL Institute of Ophthalmology, London EC1V 9EL, UK.
Tim P
TP
Levine
UCL Institute of Ophthalmology, London EC1V 9EL, UK. Electronic address: c.futter@ucl.ac.uk.
Clare E
CE
Futter
D017305:Annexin A1 / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D057146:Multivesicular Bodies / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D000098825:Oxysterol Binding Proteins
D017305:Annexin A1; D008077:Lipoproteins, LDL; D011987:Receptors, Steroid; C114051:VAPA protein, human; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D000098825:Oxysterol Binding Proteins; D004815:Epidermal Growth Factor; D002784:Cholesterol; D066246:ErbB Receptors; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1