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

W. Mike Henne, Lu Zhu, Zsolt Balogi, Christopher Stefan, Jeffrey A. Pleiss, Scott D. Emr

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)541-551
Number of pages11
JournalThe Journal of cell biology
Volume210
Issue number4
DOIs
StatePublished - Aug 17 2015

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Vacuoles
Endoplasmic Reticulum
Proteins
Sphingolipids
Membranes
Lysosomes
Lipid Metabolism
Genes
Fluorescence
Alleles
Communication
Lipids
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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.

In: The Journal of cell biology, Vol. 210, No. 4, 17.08.2015, p. 541-551.

Research output: Contribution to journalArticle

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. In: The Journal of cell biology. 2015 ; Vol. 210, No. 4. pp. 541-551.
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