Cargando…

Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein

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) domai...

Descripción completa

Detalles Bibliográficos
Autores principales: Henne, W. Mike, Zhu, Lu, Balogi, Zsolt, Stefan, Christopher, Pleiss, Jeffrey A., Emr, Scott D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539980/
https://www.ncbi.nlm.nih.gov/pubmed/26283797
http://dx.doi.org/10.1083/jcb.201503088
_version_ 1782386174245994496
author Henne, W. Mike
Zhu, Lu
Balogi, Zsolt
Stefan, Christopher
Pleiss, Jeffrey A.
Emr, Scott D.
author_facet Henne, W. Mike
Zhu, Lu
Balogi, Zsolt
Stefan, Christopher
Pleiss, Jeffrey A.
Emr, Scott D.
author_sort Henne, W. Mike
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4539980
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-45399802016-02-17 Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein Henne, W. Mike Zhu, Lu Balogi, Zsolt Stefan, Christopher Pleiss, Jeffrey A. Emr, Scott D. J Cell Biol Research Articles 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. The Rockefeller University Press 2015-08-17 /pmc/articles/PMC4539980/ /pubmed/26283797 http://dx.doi.org/10.1083/jcb.201503088 Text en © 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/).
spellingShingle Research Articles
Henne, W. Mike
Zhu, Lu
Balogi, Zsolt
Stefan, Christopher
Pleiss, Jeffrey A.
Emr, Scott D.
Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein
title Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein
title_full Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein
title_fullStr Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein
title_full_unstemmed Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein
title_short Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein
title_sort mdm1/snx13 is a novel er–endolysosomal interorganelle tethering protein
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539980/
https://www.ncbi.nlm.nih.gov/pubmed/26283797
http://dx.doi.org/10.1083/jcb.201503088
work_keys_str_mv AT hennewmike mdm1snx13isanovelerendolysosomalinterorganelletetheringprotein
AT zhulu mdm1snx13isanovelerendolysosomalinterorganelletetheringprotein
AT balogizsolt mdm1snx13isanovelerendolysosomalinterorganelletetheringprotein
AT stefanchristopher mdm1snx13isanovelerendolysosomalinterorganelletetheringprotein
AT pleissjeffreya mdm1snx13isanovelerendolysosomalinterorganelletetheringprotein
AT emrscottd mdm1snx13isanovelerendolysosomalinterorganelletetheringprotein