The ER in budding yeast (colored lines) has less cortex (red) and more cytoplasmic (yellow) association when Scs2 is missing (bottom). Nuclear-associated ER (blue) appears normal.
The positioning of particular organelles can often be important for cell function. How a cell senses organelle positioning, however, is unknown. The budding yeast is a useful model organism for getting to the bottom of this question, as its organelles move into the bud in a highly ordered manner. The ER, for example, travels along actin cables into the bud, and then attaches to the bud tip and spreads around the cortex.
Sites of contact between the ER and the plasma membrane are enriched in an ER transmembrane protein called Scs2. Loewen et al. now show that Scs2 probably links the two membranes together. ER cortical distribution, they found, was abnormal in yeast lacking the protein. This phenotype was exaggerated in the bud. The team shows that this more serious defect occurs because Scs2 is normally enriched at the bud tip, where it is needed to set up the initial attachment point for the ER.
In the Scs2 mutants, cell division often arrested before cytokinesis. Cytokinesis requires the formation of a ring of cytoskeletal septin proteins around the bud neck. But in Scs2 mutants, the septins were disorganized. Septin disorganization sets off a pathway known to halt the cell cycle. The team suggests that cells activate this pathway to stall division until the ER is correctly located in the bud. How the mispositioned ER interrupts proper septin deposition is yet unclear. One possibility is that a septin regulator called Cdc28, which is found on the ER, is in the wrong position to operate correctly.
The authors also found that the human homologue of Scs2, called VAP, shares the same unique polarized distribution in yeast, suggesting a conserved function. VAP mutations are associated with the motorneuron disease amyotrophic lateral sclerosis. Whether wrongly placed ER in the neurons of these patients could be part of the cellular pathology—perhaps by perturbing neurotransmitter vesicle release—remains to be seen. 
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