Analysis of Bulk Lipid Transport at Membrane Contact Sites

ABSTRACT All eukaryotic cells face the critical problem of regulating the subcellular distribution of lipids. The lipid composition of organelle membranes is distinct, with each membrane containing a specific subset of lipids that defines organelle identity and regulates organelle function. These membrane lipids are also critical for intracellular signaling pathways and for proper control of lipid metabolism. Not surprisingly, defects in the subcellular distribution or metabolism of these macromolecules underlie many devastating human diseases. We recently identified and unified a novel family of proteins: the bridge-like lipid transfer proteins (BLTPs). BLTPs are very large, rod-shaped proteins with uninterrupted inner hydrophobic channels that serve as lipid superhighways between apposing membranes at organelle contact sites. Although mutations in BLTPs are associated with human disease, BLTPs are not required for single cell viability, a fact that has limited efforts to understand how disruption of BLTP function contributes to disease. Our goal in this proposal is to use an animal context to tackle this gap and, in doing so, uncover the biological significance of BLTPs—and bulk lipid transport—to physiology and disease. We identified a Drosophila model system where disruption of a single BLTP, BLTP2, results in dramatic physiological and cellular phenotypes, leaving us uniquely poised to systematically dissect the molecular and cellular functions of this protein and understand how BLTP dysfunction leads to disease. We will pursue the following two specific aims: 1) Define the essential molecular properties of BLTP2. 2) How is BLTP2 function at membrane contact sites regulated? Our long-term goal is to understand BLTP function and how regulation of bulk lipid transport impacts animal physiology. We expect our studies to reveal essential insights into the role of BLTPs in human disease which, in turn, we hope will lead to novel therapies to treat disorders caused by BLTP dysfunction.