Audhya Lab
Lipid Signaling
Cellular membranes are composed of numerous lipid species that function together to maintain subcellular compartmentalization and recruit downstream effector proteins. In particular, acidic phospholipids, including phosphorylated derivatives of phosphatidylinositol (PIPs) and phosphatidylserine (PS), are ideally suited to bind positively charged peptide sequences within peripheral membrane proteins, often activating these effectors to carry out their specific function(s). Using domains that uniquely recognize particular lipid head groups, a distribution map of PIPs and PS has evolved, highlighting important roles for PI3P at early endosomes, PI4P at the Golgi, and PI4,5P2 and PS at the plasma membrane of C. elegans embryos and human tissue culture cells. Using a variety of biochemical and genetic approaches, we are studying the roles of lipid signaling in regulating key steps of membrane reorganization, which is necessary for vesicle formation throughout the endomembrane system.

Changes in lipid composition can alter bilayer topology and promote curvature during vesicle biogenesis and membrane tubulation. In particular, members of the phospholipase A2 (PLA2) superfamily cleave the sn-2 acyl bond of phospholipids and release two biologically active molecules, a lysophospholipid and a free fatty acid. Importantly, lysophospholipids can dramatically impact membrane architecture. More specifically, an increased local concentration of lysophospholipid density in a lipid bilayer can generate or stabilize membrane curvature by introducing cone-shaped molecules into a relatively flat surface. Independently, the released fatty acid can function as a second messenger in cell signaling. For example, arachidonic acid liberated from PLA2-mediated hydrolysis of membrane phospholipids has been shown to alter the activity of ion channels and protein kinases in neurons, which affect their excitability. Additionally, arachidonic acid is a precursor for eicosanoid production, which regulates the inflammatory response and other signal transduction events. Using biochemical and biophysical approaches, we are investigating the functions of a group of calcium-independent PLA2 enzymes that have been implicated both in organelle remodeling and membrane trafficking. Our ultimate goal is to understand how these factors function together with membrane bending proteins to orchestrate temporally and spatially regulated membrane remodeling events.