Mdm1 helps the ER and vacuole stay in touch

Mdm1 helps the ER and vacuole stay in touch 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 cer-ebellar 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 sphingo-lipids 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. miR-7 loss is hard to stomach Zhao et al. reveal that the microRNA miR-7 suppresses gastric cancer by inhibiting NF-κB signaling, and that this protective mechanism is compromised by the cancer-causing bacterium Helico-bacter pylori. miR-7 is frequently down-regulated in gastric cancers and can suppress gastric cell metastasis by inhibiting the growth factor receptor IGF1R. Whether miR-7 also suppresses earlier stages of gastric carcinogenesis is unknown, however, so Zhao et al. screened for new targets of the microRNA. The researchers found that miR-7 directly targets RELA and FOS, which encode transcription factors involved in the pro-oncogenic NF-κB and AP-1 signaling pathways, respectively. In human gastric cancer samples, low miR-7 levels correlated with elevated RELA and FOS expression and poor patient survival. Overexpressing miR-7 reduced RELA and FOS levels and inhibited both gastric cell proliferation and tumor growth …