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

W Mike Henne1, Lu Zhu2, Zsolt Balogi2

  • 1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Mike.Henne@utsouthwestern.edu sde26@cornell.edu.

The Journal of Cell Biology
|August 19, 2015
PubMed

Insights

Phox (PX) domain-containing protein Mdm1 acts as a novel tether between the endoplasmic reticulum (ER) and vacuole/lysosome. This discovery reveals Mdm1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Endolysosomal trafficking is crucial for cellular function but its regulation and coordination with metabolism remain unclear.
  • Identifying key regulators of endomembrane dynamics is essential for understanding cellular processes.

Purpose of the Study:

  • To identify novel genes involved in endomembrane dynamics and interorganelle communication.
  • To characterize the function of Phox (PX) domain-containing protein Mdm1 in endolysosomal trafficking and membrane contact sites.

Main Methods:

  • Global fluorescence-based genetic screen to identify endomembrane effector genes.
  • Localization studies using microscopy to determine Mdm1's position within the cell.
  • Analysis of Mdm1 truncations and their impact on ER-vacuole tethering and sphingolipid metabolism.

Main Results:

  • Mdm1 was identified as a novel interorganelle tethering protein at endoplasmic reticulum (ER)-vacuole/lysosome membrane contact sites (MCSs).
  • Mdm1 tethers the ER to the vacuole via its lipid-binding PX domain and its overexpression leads to hypertethering.
  • Mdm1 and its paralogue Nvj3 localize to ER-vacuole MCSs independently of the known tether Nvj1; Mdm1 truncations disrupt tethering and sphingolipid metabolism.

Conclusions:

  • Mdm1 functions as a critical tether at ER-vacuole MCSs, regulating interorganelle communication.
  • Mdm1's role in sphingolipid metabolism highlights its importance in lipid homeostasis.
  • Human Mdm1 homologues may have significant, previously unrecognized roles in cellular communication and lipid metabolism.

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