Developmental Biology, Genetics
National Institute of Biological Sciences, Beijing
Dr. Wang is an associate investigator at the National Institute of Biological Sciences, Beijing, China.
Regulation of Apoptotic Cell Clearance
Cells often sacrifice themselves for the good of the organism, but their remains can provoke inflammation and even trigger an immune system malfunction. Xiaochen Wang wants to work out how cells recognize and clear away cellular corpses before they cause harm. “The proper removal of these cells is critical for maintaining homeostasis of healthy tissues,” she says.
As a graduate student at Peking University, Wang’s early scientific interests focused on a broader kind of balancing act: the relationships between plants and other organisms. There she studied the complex partnership between the orchid Gastrodia elata, which is used in traditional Chinese medicine, and the fungus Armillaria mellea. The fungus provides the orchid with food and enables it to reproduce. However, the two don’t live together in perfect harmony. Wang and her colleagues discovered that the plant permits the fungus to enter only certain parts of its body and keeps its helper in check with a toxic compound known as gastrodianin.
At the same time, some of Wang’s colleagues were studying the less cooperative relationships between plants and their pathogens. One way plants resist disease is by prompting their attackers to commit cell suicide, or apoptosis. Toward the end of her graduate studies, Wang became fascinated by cell death as a defense mechanism. To pursue her interest she took a postdoctoral position with molecular biologist Ding Xue at the University of Colorado, Boulder.
Although apoptosis is often beneficial for an organism—removing a potentially cancerous cell, for instance—the corpses are a problem. They can unleash inflammation, and immune cells sometimes mistake the cellular debris for an invading pathogen, leading to a misdirected attack on the body’s own tissues. To spur their own removal, suicidal cells typically display signals that prompt the body’s cleanup cells to devour them.
In nematodes, the research model in Xue’s lab, a big player in the mechanism to detect suicidal cells is the protein WAH-1, which is a counterpart of a human protein that induces apoptosis. Wang found that WAH-1 helps the cell chop up its DNA, a key step in apoptosis. Her work also revealed that WAH-1 teams up with another protein that helps flag down the body’s cleanup cells by raising the molecule phosphatidylserine (PS) to the cell’s surface. Researchers had previously discovered that PS, which directs other cells to eat the dying cell, made this journey, but Wang’s results helped explain how.
Since becoming an assistant investigator at the National Institute of Biological Sciences in Beijing in 2006, Wang has continued her hunt for the mechanisms that control consumption of apoptotic cells. She and her colleagues have identified a “bridging molecule,” TTR-52, that connects the PS on a suicidal cell to a receptor on the potential cleanup cell. Why cells need both PS and TTR-52 for identifying cell corpses is unknown, but they might provide a margin of safety to prevent the destruction of living cells.
“You might need more than one recognition mechanism to ensure that OK, this is really an apoptotic cell that needs to be cleared,” Wang notes. It also might explain how receptors on the surface of the cleanup cell, which are not the right shape to attach to PS, actually recognize an apoptotic cell, she says.
Wang is also investigating what happens once a cellular corpse has been devoured and has to be digested. Digestion occurs in a cellular structure called the phagolysosome, analogous to a stomach, that forms when several other kinds of intracellular containers fuse. In several recent papers, Wang’s group explored how a group of enzymes called RabGTPases help control digestion. For example, one enzyme spurs the containers to fuse with each other. Among the questions Wang wants to answer is how these enzymes do their jobs.
Wang and her colleagues have uncovered six genes that take part in clearing apoptotic cells, and they are searching for others. That her work illuminates only the smallest part of the mysteries of cell suicide does not dilute Wang’s satisfaction. “Whenever you have something new, it’s a discovery,” she says. “They each make me very excited.”