Abstract 1120 The conserved protein Yet3/Bap31 is a pan-contact site lipid regulator

The central role of organelles as insulators of biochemical reactions also gives rise to their biggest functional complexity, the need to communicate and collaborate with other organelles. One way of communication is through contact sites, specialized zones of proximity between membranes of two organelles. In our previous work, we found an Endoplasmic Reticulum (ER) intermembrane protein of unknown function, Yet3, in a screen for contact site residents in yeast. So far, there has been no known function for yeast Yet3 or its human homolog Bap31, which takes part in multiple pathways in the cell and is involved in many diseases. We discovered that Yet3 ubiquitously locates to contact sites of the ER, where it functions as a scramblase. By binding all the post-squalene ergosterol biosynthesis pathway proteins, it creates sterol-rich domains that are known to be essential for contact site functions. Indeed, ergosterol levels are affected by Yet3 levels, leading to changes in the plasma membrane integrity and stability of amino acid permeases and transporters. We show that these changes dramatically alter cell metabolism, affecting the structure and function of all major organelles. Taken together, our data places Yet3 as a master metabolic regulator that through its activity at contact sites, shapes the metabolism of fats and amino acids and balances respiration and trafficking. A molecular understanding of this protein gives new insights into its role in development and pathology.