Chemical Biology of Membranes
The Chemical Biology of Membranes research group, headed by Dr. Denisa Jamecna, investigates cellular lipid transport. Using synthetic lipid-like molecules, we study how lysosomes, cellular recycling organelles, distribute various lipids such as sterols and sphingolipids throughout membranes.
Lysosomes help maintain cellular lipid membranes
The cell, similar to a human body, contains different compartments called organelles. Cellular organelles are delineated from the internal environment of the cell by an organized structure made of lipids, called a lipid membrane. Lipid membranes consist of a wide variety of structurally diverse lipids, such as phospholipids, sterols and sphingolipids. Each cellular organelle has a characteristic membrane composition.
Lysosomes are cellular organelles responsible for digesting food-derived lipids and incorporating them into cellular membranes. They also digest old membrane material from the cell itself and recycle lipid molecules for renewed use in membrane synthesis. Lysosomes thus mediate major lipid fluxes essential for cellular health and proper cell function. Perturbation in lysosomal lipid transport results in severe pathologies called lysosomal storage diseases such as Niemann Pick type C disease, in which lipids are stuck inside lysosomes.
How do we study lysosomal lipid transport?
In our lab, we study lysosomal lipid transport using cultured cells as model organism. Intracellular lipids are transported between lysosomes and other organelles via dedicated protein transporters called lipid transfer proteins. Lipid transfer proteins are selective for particular lipids, creating distinct lipid flows across the cell. Although lipids are difficult to visualize, we can observe lipid transport using highly specialized synthetic molecules called lipid analogs. Lipid analogs have a structure that is very similar to natural lipids but contains small modifications that allow diverse chemical manipulations. For example, they can be selectively stained with fluorescent markers using so called ‘click’ chemistry, allowing a direct visualization of lipids in living cells. Our lab synthesizes our own lysosomal lipid analogs for studies of sterol and sphingolipid transport.
Mechanisms of sterol and sphingolipid transport at the lysosome
Many lipid transfer proteins can specifically transport more than one lipid. Our research focuses on the lipid transfer protein STARD3. STARD3 is localized within contact sites between the lysosomes and the endoplasmic reticulum (ER). It is involved in trafficking of both cholesterol and sphingosine. We want to understand how STARD3’s activity influences lysosomal lipid flows and cellular lipid homeostasis. In addition, we aim to find out how cells organize the molecular environment around STARD3 to maintain the complicated task of delivering structurally diverse lipids within the narrow lysosome-ER contact site. Our overarching goal is to understand which cellular machineries regulate the balance between sterols and sphingolipid trafficking and what are the molecular rules governing this vital process. Understanding these open questions can help us shed light on the pathology of lysosomal storage disorders and other diseases manifesting a lysosomal lipid dysfunction.
