Glucose starvation signaling via nucleus-vacuole junction remodeling controls ergosterol synthesis

Membrane contact sites, where organelle membranes come into close proximity, function as dynamic hubs for lipid metabolism in response to metabolic and stress signals. In yeast, the nucleus-vacuole junction (NVJ) expands during glucose starvation (GS) through the recruitment of stress-specific proteins; however, the underlying mechanisms and physiological significance have remained unclear. Here, we identify the aspartyl protease Ypf1 and the yeast INSIG homologs Nsg1 and Nsg2 as NVJ-localized proteins specifically recruited during GS. Ypf1 promotes the recruitment of Nsg1, Nsg2, and the HMG-CoA reductases Hmg1 and Hmg2 to the NVJ, likely in association with changes in nuclear membrane lipid composition caused by suppression of fatty acid elongases. This remodeling destabilizes Nsg1, thereby activating Hmg1, while stabilizing Nsg2, which suppresses Hmg1 to fine-tune sterol synthesis. Loss of both Nsg1 and Nsg2 leads to hyperactivation of Hmg1 and accumulation of squalene, a sterol biosynthetic intermediate. We propose that suppression of fatty acid elongases drives GS-dependent NVJ remodeling to regulate ergosterol synthesis.