Mdm1 (green) localizes to the sites where vacuoles (V) contact the ER (red) surrounding nuclei (N).

Mdm1 (green) localizes to the sites where vacuoles (V) contact the ER (red) surrounding nuclei (N).

Henne et al. reveal that a protein linked to human neurological disease regulates sphingolipid metabolism in yeast by tethering vacuoles to the ER.

Little is known about yeast Mdm1, but it is homologous to several mammalian sorting nexins, including SNX14, which is mutated in an autosomal-recessive form of cerebellar ataxia. Henne et al. identified Mdm1 in a screen for proteins that regulate endocytic trafficking to the yeast lysosome, or vacuole.

Surprisingly, however, Mdm1 didn’t localize to endosomes. Instead, the protein accumulated at the sites where vacuoles contact the ER membranes surrounding the nucleus. Overexpressing Mdm1 enlarged these nuclear ER–vacuole junctions (NVJs), suggesting that the protein helps tether these two organelles to each other. Indeed, Henne et al. found that two N-terminal transmembrane domains anchored Mdm1 in the ER, while a C-terminal PX domain bound to phospholipids on the vacuole surface. A truncated version of Mdm1 that, similar to a disease-causing SNX14 allele, lacked the PX domain failed to localize to NVJs.

NVJs have previously been implicated in lipid metabolism, and the cells of patients with SNX14 mutations appear to accumulate lipids in cytoplasmic granules. Henne et al. found that yeast expressing the truncated version of Mdm1 were hypersensitive to an inhibitor of sphingolipid synthesis, suggesting they were somehow defective in sphingolipid metabolism. Because sphingolipids are required for efficient endocytosis, this could explain why endosomal trafficking is delayed in mdm1Δ yeast. Lead author Mike Henne now wants to investigate how defects in vacuole–ER contacts and sphingolipid metabolism contribute to the symptoms of humans with SNX14 mutations.

References

References
Henne
,
W.M.
, et al
.
2015
.
J. Cell Biol.

Author notes

Text by Ben Short