AXEL NOHTURFFT: NEW INSIGHTS INTO MEMBRANE BIOLOGY
February 21st, 2006
To understand Axel Nohturfft’s fascination with cell membranes, think of a time billions of years ago, when life first flickered in a primordial soup, bubbling on a new earth. Some primitive molecules—structured as fatty substances called lipids—began to agglomerate into little bags of membranes that ultimately morphed into the ancestors of modern cells. By this process, the primordial soup was canned, so to speak, creating individuals that could compete with each other for nutrients and space, and setting the stage for an evolutionary path that spread life throughout the planet.
Nohturfft, who recently was promoted to MCB Associate Professor, alludes to life’s origins as he describes what fascinates him about cell membranes. "By studying membrane biogenesis we explore one of life’s fundamental aspects," he explains. "If you want to understand cell biology then you have to know how cells and organelles within cells are constructed. Membranes define the cell and its internal structures—without them, the cell material is just a blob."
In addition to providing fundamental insights into the assembly of membranes, Nohturfft’s research also promotes biomedical advances. His studies of lysosomes, which are intracellular organelles loaded with molecule-chewing hydrolytic enzymes, have provided insights into atherosclerosis—a disease that occurs when lysosomes accumulate so much cholesterol that afflicted cells die. In another applied area, he investigates phagocytosis, which is how immune cells engulf and kill harmful microbes. "Among the different cellular membranes I’m particularly interested in are endosomes, lysosomes, and phagosomes, which are all part of the same family of organelles," Nohturfft says. "We’re studying how the synthesis of these organelles is controlled and coordinated."From Germany to the United States
After finishing his undergraduate degree at the Free University of Berlin, Nohturfft traveled to Canada, where he spent the early 1990s doing research at the University of Victoria in British Columbia. From there, he immigrated to the United States for a PhD in biochemistry, which he completed at the University of Texas Southwestern Medical Center in Dallas in 1998.
While working with UT Professors Joseph Goldstein and Michael Brown, Nohturfft discovered something that sparked his lasting interest in lipids and membranes. He was studying a protein called SCAP that resides in the endoplasmic reticulum, an intracellular protein and membrane factory. Nohturfft showed that SCAP plays a crucial role in cholesterol synthesis: when cholesterol levels are low, SCAP leaps into action—it binds with another protein called SREBP, and together the proteins depart for an organelle called the Golgi apparatus. Once there, SREBP is split into fragments, one of which penetrates the cell nucleus to activate genes required for cholesterol production. SCAP is a cholesterol sensor: when levels are high, it keeps SREBP out of the Golgi and the nucleus, throttling cholesterol production.A New Focus
With this finding, Nohturfft paved the way for a job as MCB Assistant Professor, which he began in 2001. Upon arriving at Harvard, his interests began to shift: rather than focusing further on SCAP, Nohturfft turned his attention to lipid distribution within cells, and the mechanisms behind membrane biogenesis. He started with some baseline assumptions: For example, he knew cholesterol and other lipids—particularly phospholipids—play complementary roles in membrane development. And he hypothesized that their interactions are cross-regulated, so that phospholipid production, for example, depends on cholesterol production, and vice versa. The ultimate goal, he says, was to study how lipid components "talk to each other" while membranes are being made. But there was a problem: membrane biogenesis is intimately connected to cell growth and division. To study it as an isolated process, he would have to somehow uncouple it from cell growth, which is no easy task.
Fortunately, the phagocytic cells of the immune system offered a solution. These cells engulf bacteria and viruses and then wrap the microbes in a membranous sheath called a phagosome. Thus, phagocytes make membranes even when they themselves aren’t growing. Nohturfft tricks phagocytes into making membrane by feeding them latex beads, which the unsuspecting cells promptly engulf as if they were microbes. For mysterious reasons that Nohturfft says he doesn’t yet understand, the phagocytes produce additional membranes in amounts that specifically match the surface area of the internalized particles. This provides him with a model system for studying membrane biogenesis. "We can inhibit cholesterol or phospholipid synthesis and ask, how does this cross-regulation work?" Nohturfft says. "That’s a research method we’re using now and one we plan to be using for a while."
Nohturfft also studies phagocytosis as a real-life function of the immune system. When a microbe gets pulled into an immune cell, its phagosome carrier fuses with a lysosome that promptly delivers a killing blast of hydrolytic enzymes. To isolate this process, Nohturfft extracts phagosomes and mixes them with lysosomes in a test tube. With this system, he has identified the early "tethering and docking" steps that precede the actual fusion of the two organelles. He’s now building on this finding by studying the proteins that govern the process. Nohturfft says the research offers biomedical opportunities: Some dangerous bacteria outwit the immune system by blocking the phagosome/lysosome union, he says. "And we think that in some cases this interference might be at the tethering and docking level," he adds. "If this happens, the phagosomes and lysosomes never interact, allowing the bacteria to survive within the cell. So, our work provides new tools and perspectives in this area that will be useful to researchers who study the pathology of microbial infections."
Meanwhile, Nohturfft’s research on cholesterol metabolism has made important strides. Cholesterol in the cell typically exists in one of two forms: either as the free lipid in membranes, or bound to fatty acids as a cholesterol ester. The latter form constitutes one component of low-density lipoprotein (LDL), which is the primary cholesterol-carrying substance in the blood. Upon entering a cell, LDL is transported to lysosomes that hydrolyze it back to its cholesterol and fatty acid components. In this way, the cell liberates cholesterol to make it available for membrane production. But in atherosclerosis—which can be a precursor to heart disease—this process is blocked. Instead of being hydrolyzed, cholesterol ester accumulates in lysosomes, so that the free lipid can’t go out and build membranes like it’s supposed to.
The cause of this accumulation long mystified researchers until Nohturfft identified a mechanism. According to his findings, hydrolysis of the cholesterol ester is driven by the membrane’s capacity to absorb free cholesterol—if membrane levels are low, the lysosome releases more, and if the levels are high, the cholesterol stays in the lysosome in the esterified form. Nohturfft speculates that the membranes in atherosclerotic cells are saturated with cholesterol, and that this saturation prevents the release of free cholesterol from lysosomes. "Because cholesterol is water-insoluble, it has nowhere to go," he explains. "And our data provided an attractive model for why lysosomal cholesterol ester accumulation might happen in human cells."
Looking forward, Nohturfft says he’s pleased with his professional prospects. "Harvard is a great place to work," he says. "And I like to teach," he adds. "The students at Harvard are excellent. And teaching helps me keep an eye on the big picture."