- Editorial Boards: The Journal of Cell Biology, Developmental Cell, The Journal of Biological Chemistry, Contact
- Senior Investigator, 2008-present
- Tenure-Track Investigator, 2001-2008
- Postdoctoral Fellow, Harvard University, advisor, Tom Rapoport, 1996-2001
- Ph.D., Harvard University, 1996
The ultimate purpose of our research is to understand organelle biogenesis.
The main research focuses of my lab are organelle biogenesis and the roles of membrane contact sites in intracellular lipid homeostasis. We are particularly interested in de novo organelle biogenesis, which primarily occurs in the ER. There are three interrelated projects in the lab.
Lipid droplet and lipoprotein biogenesis
Lipid droplets (LDs) are lipid storage organelles found in almost all cell types. They contain a core of neutral lipids, such as triglyceride and cholesteryl ester, surrounded by a monolayer of phospholipids and proteins. Nascent LDs form in the ER. The earliest step is thought to occur when neutral lipids in the ER bilayer undergo a phase transition, forming lens-like structures that grow into mature LDs. Accumulating evidence suggests this process occurs at specialized sites in the ER that are enriched in proteins such as seipin, LDAF1, perilipins, and MCTP2. We are studying the earliest steps of LD biogenesis using model membranes and in vivo approaches.
Apolipoprotein B (ApoB)-containing lipoproteins are assemblies of proteins and lipids that are like LDs but are secreted from cells. These particles transport dietary and endogenous lipids through the circulation. The most abundant lipoprotein in plasma is low density lipoprotein (LDL), which is metabolically derived from very low-density lipoproteins (VLDL) produced by hepatocytes in the liver. While ApoB-containing lipoproteins are essential, elevated levels in plasma contribute to prevalent metabolic diseases, including atherosclerosis, type 2 diabetes, and obesity. Developing effective therapies to safely reduce levels of these lipoproteins in plasma is a major public health goal. ApoB is required for VLDL assembly and secretion. Despite years of study, there are still major gaps in our understanding of how ApoB is lipidated and how lipoproteins are trafficked, degraded, and mature in cells. We are taking a variety of approaches to identify proteins that facilitate VLDL biogenesis.
Peroxisomes are membrane-bound organelles that have important roles in the metabolism of lipids, polyamines, D-amino acids, and fatty acid β oxidation. They are found in most cell types and a number of rare autosomal disorders are caused by defects in peroxisome biogenesis or function. Nascent peroxisomes are produced in the ER, where pre-peroxisome vesicles bud from the ER and mature into functional peroxisomes. We are using a variety of approaches to investigate early stages of peroxisome biogenesis in mammalian cells.
Lipid trafficking at membrane contact sites
Organelles communicate and integrate their activities by forming close contacts, often called membrane contact sites (MCSs). Interest in MCSs has grown dramatically in the past decade as it is has become clear that they are ubiquitous and have a much broader range of roles in cells than was initially thought. MCSs are sites where signals and small molecules, such as lipids, are exchanged between organelles. My laboratory studies the mechanism and function of lipid exchange at MCSs using biochemical and cell biological approaches. Current work focuses on a group of large proteins that are tube-like and are thought to allow lipids to flow between membranes. Mutations in these proteins cause several rare neurodevelopmental disorders and other diseases. We are studying how these proteins function in mammalian cells and in yeast. We are also working to understand how the structure and biophysical properties of MCSs regulates lipid exchange.
Applying our Research
Defects in lipid metabolism and organelle biogenesis are associated with numerous diseases. Gaining insight into the basic processes in cells will help us understand how defects in them contribute to human disease.
Need for Further Study
There are many open questions in all these projects.
- Vps13-like proteins provide phosphatidylethanolamine for GPI anchor synthesis in the ER.
- Toulmay A, Whittle FB, Yang J, Bai X, Diarra J, Banerjee S, Levine TP, Golden A, Prinz WA.
- J Cell Biol (2022 Mar 7) 221. Abstract/Full Text
- Retinyl esters form lipid droplets independently of triacylglycerol and seipin.
- Molenaar MR, Yadav KK, Toulmay A, Wassenaar TA, Mari MC, Caillon L, Chorlay A, Lukmantara IE, Haaker MW, Wubbolts RW, Houweling M, Vaandrager AB, Prieur X, Reggiori F, Choudhary V, Yang H, Schneiter R, Thiam AR, Prinz WA, Helms JB.
- J Cell Biol (2021 Oct 4) 220. Abstract/Full Text
Research in Plain Language
Eukaryotic cells have organelle – internal structures that are somewhat like organs in animals. My lab is working on understanding how cells make organelles, a process called organelle biogenesis. We are particularly focused on the biogenesis of organelles that play critical roles in lipid metabolism.
The movement of lipids in cells
Most organelles are membrane-bound structures in cells. These membranes are composed of lipids and proteins. We are working to understand how cells move lipids between organelles and how these processes contribute to lipid metabolism and cell function. We are particularly interested in how cells exchange lipids at regions where organelles come in close contact. Understanding how this occurs is not only an important problem in cell biology, but many rare diseases are caused by defects in the proteins that exchange lipids at sites where organelles are in close contact.
Biogenesis of lipid droplets and lipoproteins
Cells and animals need to store excess fats, also called lipids. In cells, fats are stored in structures called lipid droplets. Similar structures, known as lipoproteins, transport dietary fats through the circulation to the various tissues in the body. Because lipids are insoluble in water, they are stored and transported in special particles that have a core of lipids and proteins on the outside. We are working to understand how these particles are made in cells. Elevated level of lipoproteins in the circulation or lipid particles in cells contribute to prevalent metabolic diseases, such as atherosclerosis, type 2 diabetes, obesity, and some lipodystrophies, rare syndromes that cause people to lose fats in some organs. We hope our work will lead to the development of effective therapies to safely reduce levels of lipoproteins in the circulation and treat lipodystrophies.