A Cell’s ability to sense and respond to changes in nutrient levels is an essential component of homeostasis. Careful control of the amount and affinity of transporters on the cell surface underlies the fine balance between optimal uptake and early sensing of nutrient deprivation. We discovered that a yet uncharacterized yeast gene encodes an intramembrane aspartic protease active on the ER membrane. Due to structural similarity to the human Presenilin protease, we named this protease YPF1 (Yeast Presenilin-Fold protease). We identified that this protease is at the core of a post translational regulation step on the amount of cell surface expression of transporters. Specifically, Ypf1 mediates the degradation of high affinity transporters such as Zrt1 (zinc) and Pho84 (phosphate). Ypf1 is constitutively active in nutrient-rich medium thus carefully controlling the number of transporters such that early sensing of nutrient depletion is enabled. In contrast, Ypf1 mediated degradation is aborted under ensuing starvation to enable a rapid elevation of high-affinity transporters. The rapid nature of the post-translational response gives the cell a dramatic advantage in nutrient uptake under starvation conditions, long before a transcriptional response can be fully developed. Indeed, we show that activity of this regulatory mechanism is required for early detection of nutrient depletion. Hence, in cells deleted for Ypf1 activity we find delayed preparation for, and impaired recovery from nutrient starvation.
