Henne, WM;
Zhu, L;
Balogi, Z;
Stefan, C;
Pleiss, JA;
Emr, SD;
(2015)
Mdm1/Snx13 is a novel ER-endolysosomal interorganelle tethering protein.
The Journal of Cell Biology
, 210
(4)
pp. 541-551.
10.1083/jcb.201503088.
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Abstract
Although endolysosomal trafficking is well defined, how it is regulated and coordinates with cellular metabolism is unclear. To identify genes governing endolysosomal dynamics, we conducted a global fluorescence-based screen to reveal endomembrane effector genes. Screening implicated Phox (PX) domain-containing protein Mdm1 in endomembrane dynamics. Surprisingly, we demonstrate that Mdm1 is a novel interorganelle tethering protein that localizes to endoplasmic reticulum (ER)-vacuole/lysosome membrane contact sites (MCSs). We show that Mdm1 is ER anchored and contacts the vacuole surface in trans via its lipid-binding PX domain. Strikingly, overexpression of Mdm1 induced ER-vacuole hypertethering, underscoring its role as an interorganelle tether. We also show that Mdm1 and its paralogue Ydr179w-a (named Nvj3 in this study) localize to ER-vacuole MCSs independently of established tether Nvj1. Finally, we find that Mdm1 truncations analogous to neurological disease-associated SNX14 alleles fail to tether the ER and vacuole and perturb sphingolipid metabolism. Our work suggests that human Mdm1 homologues may play previously unappreciated roles in interorganelle communication and lipid metabolism.
| Type: | Article |
|---|---|
| Title: | Mdm1/Snx13 is a novel ER-endolysosomal interorganelle tethering protein |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1083/jcb.201503088 |
| Publisher version: | http://dx.doi.org/10.1083/jcb.201503088 |
| Language: | English |
| Additional information: | Copyright © 2015 Henne et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
| Keywords: | Binding Sites, Endoplasmic Reticulum, Endosomes, Intermediate Filament Proteins, Lysosomes, Protein Binding, Protein Structure, Tertiary, Protein Transport, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sphingolipids, Vacuoles |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1484227 |
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