"Sugar-coating" on proteins may safeguard body against further insult. M.D.-Ph.D. student show mannose receptors performs clearance role.

Much like a cadre of emergency workers at the scene of an accident, the body's immune system cells gather at the site of an injury, whether it is a simple cut or an infection. This micro-scopic crowd largely consists of inflammatory cells and proteins, and together they marshal the immune system's arsenal to bring the offending stimulus under control.

And as so often occurs at the scene of an accident, the crowd lingers. Initially helpful, its presence can create new problems. At the scene of a car accident, the problem may be spectators blocking the travel of the ambulance. In the body, the crowd of inflammatory proteins and other cells can continue to attract more immune system agents than needed. To prevent such an uncontrolled response, a clean-up mechanism is needed to signal the end of the rescue operation.

Now, for the first time, Rockefeller researchers have found that a receptor protein called the mannose receptor on liver endothelial cells performs such a function, which may be important in preventing further damage to healthy tissues.

Sena Lee, a biomedical fellow in the Tri-institutional M.D.-Ph.D. Program, published part of her thesis research on the clearance activity of the mannose receptor in the March 8 issue of Science. Michel Nussenzweig, Howard Hughes Medical Institute investigator and head of the Laboratory of Molecular Immunology, is Lee's advisor and a co-author of the publication.

Like emergency workers who wear similar garb so that they may be easily identified, many inflammatory proteins congregating at injury sites in the body carry similar tags made of sugars. "In this setting, the sugar tag, called high-mannose glycan, is a marker for the proteins' identity," says Lee. The mannose receptor recognizes high-mannose glycan as a disposal tag. When the body no longer needs the proteins in the area, mannose receptor initiates their removal. The receptor is then down regulated, or turned off, until it is needed to perform the next job.

Lee and her colleagues' research is part of the larger field of "glyco-biology" - the chemistry and biology of carbohydrates, or sugars - which was described in a special issue of Science in 2001.

An editorial in the magazine called glycobiology" à Cinderella field: an area that involves much work but, alas, does not get to show off at the ball with her cousins, the genomes, and proteins." However, the Science contributors suggested, more and more guests at the ball will learn to recognize Cinderella. Glycobiology, including the research of Lee and her colleagues, is poised to receive well-deserved attention.

"Most biologists are interested in genes and proteins and their regulation, not in sugars. But many proteins, especially extracellular and cell membrane proteins, have sugars on them," says Lee. Some researchers have made medical progress by homing in on glycans. A recent development in HIV experimental therapy, for example, exploits the virus's dependence on its glycoprotein shell binding to a human cell surface receptor, CCR5.

"Sugar-coated" proteins, called glycoproteins, are involved in myriad activities, from regulating the immune system cells' movements and stability, to cloaking cancer cells as they navigate immunologic defenses.

"We know that many protein-protein interactions are based on glycans, but even more interesting, glycans are able to directly change the con-formation or activation level of their proteins. These modifications may be the key to understanding the functional regulation of the body's proteins," says Lee.

Using mice that were genetically deficient in the mannose receptor, Lee and her colleagues identified all the sugars that could bind to the receptor. They then induced inflammation in the normal, or wild type, and the knockout, or mutant, mice.

The experiments were designed to reveal whether the mannose receptor removes a class of circulating glyco-proteins from blood, and whether there is another bodily clearance mechanism if the receptor is lacking or disabled. The mutant mice could not clear the glycoproteins released during inflammation.

Inflammatory proteins are helpful in repairing an injury inside the body, but are no longer needed when the crisis has passed. Their presence after an injury can harm surrounding tissues. To dispose of them, mannose receptors (violet) are turned on and bind with the complex sugars (yellow) tagging the proteins. The anchoring endothelial cell then engulfs the bound proteins.

These findings indicate that the body efficiently regulates inflammatory proteins by coating them with glycans and by using receptors like the mannose receptor that recognize these glycans to retrieve the proteins when they are no longer useful.

"Sena's work is exciting because no one has ever proven that blood protein levels can be regulated by a glycan receptor this way," says Nussenzweig.

More research is required to fully understand the role of glycans and their receptors in the regulation of inflammation, but one potential avenue for biomedical applications is in pharmacokinetics. Manipulating the levels of certain proteins in the body could be achieved by altering the glycans they carry. In this way, scientists could design ways to limit or extend the circulatory lifespan of bioactive proteins.

Lee will bring laboratory research to bear on the medical practice she establishes in the future, but first she must complete her medical training. Glycobiology, the so-called "Cinderella field," will have to wait for Lee to return to the ball. - Lynn Love

Courtesy: The Rockefeller Univ. Newsletter
"News & Notes" Friday, April 12, 2002

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