Do Lipid Rafts Exist?

The contention that molecular platforms known as lipid rails sail on the cell's outer, or plasma. membrane has kept researchers debating for more than a decade. Although many scientists argue that rafts either don't exist or have no biological relevance, their supporters insist the idea remains afloat. Cell biologist Kai Simons. now at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany. and his colleague Dina lkonen christened the term "lipid raft" in a I 997 Nature paper that detailed the concept. At the time, the main model of the plasma membrane portrayed it as a sea of lipids through which proteins drifted with little or no organization.

But the duo proposed that two kinds of lipids. cholesterol and sphingolipids, huddle together in the membrane, producing stable formalions they called rafts. One line of evidence thr that concept, the team noted, was the goop left behind in test tube studies when certain detergents dissolve the plasma membrane. This so-called detergent-resistant membrane oozes with cholesterol. sphingolipids, and select membrane proteins.

Rafts serve the cell, the hypothesis suggested, because they gather in one place the proteins necessary for a particular task, such as importing material or relaying a message across the plasma membrane. Proposed passengers on the rafts included glycosylphos-ph ati dy I in os ito I (GPO-anchored prole ins. which adhere to the outer layer of the plasma membrane and perform functions such as receiving signals and helping cells stick together. The idea roiled the cell biology community. "Right away. there were two camps;' Simons says.

"One camp didn't believe a word.- But plenty of scientists hopped aboard. More than 3000 papers later, the activities attributed to lipid rafts include promoting drug resistance in cancer cells and serving as escape hatches for viruses such as the ones that cause flu. Possibly the most debated hypothesis invoked rafts to explain the activation of the T cell receptor, the cell surface protein that spurs these immune cells to action when a pathogen is on the loose in the body. Incorporating the receptor into a raft helps switch it on. studies have suggested, possibly by allowing the receptor to hobnob with other proteins necessary for stimulating the T cell or because those proteins need the raft environment to work. Members of both camps concur that the raft concept was compelling and galvanized investigation into membrane organiza-tion.

"The raft hypothesis is brilliant in some ways," says biophysical chemist Jay Groves of the University of Calitbrnia, Berkeley. "My personal opinion is that the very idea of rafts enriches scientific research' says biophysicist Sarah Keller of the University of Washington, Seattle, "whether or not rafts exist in either specific cases or more generally!' But how solid is the proof there are rafts? Skeptics abound. and they've scored some hits on the original raft evidence. Membrane biologist Michael Edidin of Johns Hopkins Uni-versity in Baltimore, Maryland, says the field has fallen victim to what he calls the "sins of detergent extraction!' Too many researchers have assumed that detergent-resistant mem-branes are genuine rafts, even though studies reveal that extraction can disrupt their compo-sition.

 "The idea of these isolatable islands of raft lipids is probably not viable," says membrane biologist Ken Jacobson of the Univer-sity of North Carolina, Chapel I fill. According to the raft hypothesis, certain lipids naturally sort themselves to create the organized pockets of proteins that make up rafts. But many researchers don't buy that mechanism for inducing order in the mem-brane. It is too passive, especially when the plasma membrane is constantly churning, says Satyaj it Mayor, a membrane biologist at the National Centre for Biological Science in Bangalore, India. Instead, he says. his group's research points to a more active pro-cess in which "the cell is using energy to con-struct regions in the membrane." Groves says the original hypothesis gave lipids too much credit—and proteins too little.

"Proteins define their own environment. Lipids almost completely follow their behavior," he says. Critics have also griped because the vital statistics of lipid rafts, such as their size and life span on a cell membrane, have proven so difficult to pin down. In an early study, Simons and colleagues estimated the d iam-eter of rafts at about 50 nanometers, or more than 3000 sphingolipid molecules across. In a 2006 attempt to sharpen the raft definition, a group of membrane researchers suggested a size range of 10 nanometers to 200 nano-meters, and other estimates have come in higher or lower. Rafts still have their supporters, how-ever. Akihiro Kusumi, a membrane biophysicist at Kyoto University in Japan. says that if researchers specify raft criteria, such as size. and spell out which isolation techniques they use, they can demonstrate structures that qualify as rafts.

For his part. Simons acknowledges the failings of detergent extraction but counters that new cell imaging techniques are adding to the evidence for rafts. Researchers using one form of super-resolution microscopy, known as stimulated emission depleted microscopy, found in 2009 that sphingolipids and GPI-anchored proteins tarried in certain molecular clusters in the membrane, as if they briefly joined rafts. Cell biologists say it's important to resolve the lipid raft debate eventually because the plasma membrane controls what enters and exits cells and how they send and receive sig-nals. Although researchers have proposed several alternatives for how the plasma membrane organizes itself, none of them has caught on. But if a better explanation rises to the surfitce, cell biologists will have to give some of the credit to rafts.

SOURCE : SCIENCE MAGAZINE VOL 334