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PMID: 27419871 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Endosome-ER Contacts Control Actin Nucleation and Retromer Function through VAP-Dependent Regulation of PI4P.

Cell ·Vol. 166 ·No. 2 ·2016-07-14 ·Pages 408-423

Dong R, Saheki Y, Swarup S, Lucast L, Harper JW, De Camilli P

Abstract

VAP (VAPA and VAPB) is an evolutionarily conserved endoplasmic reticulum (ER)-anchored protein that helps generate tethers between the ER and other membranes through which lipids are exchanged across adjacent bilayers. Here, we report that by regulating PI4P levels on endosomes, VAP affects WASH-dependent actin nucleation on these organelles and the function of the retromer, a protein coat responsible for endosome-to-Golgi traffic. VAP is recruited to retromer budding sites on endosomes via an interaction with the retromer SNX2 subunit. Cells lacking VAP accumulate high levels of PI4P, actin comets, and trans-Golgi proteins on endosomes. Such defects are mimicked by downregulation of OSBP, a VAP interactor and PI4P transporter that participates in VAP-dependent ER-endosomes tethers. These results reveal a role of PI4P in retromer-/WASH-dependent budding from endosomes. Collectively, our data show how the ER can control budding dynamics and association with the cytoskeleton of another membrane by direct contacts leading to bilayer lipid modifications.

MeSH Terms
Actins/metabolism Endoplasmic Reticulum/metabolism Endosomes/metabolism Gene Knockout Techniques HeLa Cells Humans Microfilament Proteins/metabolism Phosphatidylinositol Phosphates/metabolism Receptors, Steroid/metabolism Transcription Activator-Like Effector Nucleases Vesicular Transport Proteins/genetics,metabolism
Chemicals
Actins Microfilament Proteins Phosphatidylinositol Phosphates Receptors, Steroid VAPA protein, human VAPB protein, human Vesicular Transport Proteins WASH protein, human oxysterol binding protein phosphatidylinositol 4-phosphate Transcription Activator-Like Effector Nucleases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Dong Rui
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
Saheki Yasunori
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
Swarup Sharan
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Lucast Louise
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
Harper J Wade
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
De Camilli Pietro
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA; Kavli Institute for Neurosciences, Yale University School of Medicine, New Haven, CT 06510, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: [email protected].
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2016.06.037
Email
[email protected]
Published
2016-07-14
Pages
408-423
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4963242
Subset
IM
Grants
NCATS NIH HHS · UL1 TR001863 · United States
NINDS NIH HHS · R37 NS083524 · United States
NIDA NIH HHS · P30 DA018343 · United States
NIDDK NIH HHS · R01 DK082700 · United States
NIDDK NIH HHS · P30 DK045735 · United States
NINDS NIH HHS · R37 NS036251 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2016.06.037 PMC Full Text View journal details
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