Chasing Surprises in the Cell's Immune Response
From his first days in graduate school, Zhijian “James” Chen, Ph.D., was hooked by the beauty of the biochemical pathway of a small protein called ubiquitin, so named because it occurs in the cells of all types of organisms. At the time, during the mid-1980s, fewer than a dozen laboratories were working on how and why ubiquitin became tagged onto other proteins in the cell.
“No one expected ubiquitin would win the Nobel Prize,” Dr. Chen said, adding that three researchers studying ubiquitin did, indeed, capture the 2004 prize in chemistry.Today, every college biology major knows that chains of ubiquitin tag proteins are slated for destruction by the cell’s garbage disposal specialist, the proteasome. For the past decade, Dr. Chen has explored the intersection of the ubiquitin pathway with the cell’s immune response pathway—and he has found surprises at every turn.
“That is the fun of doing science—finding unexpected things,” said Chen, a 2002 BWF Investigator in the Pathogenesis of Infectious Disease, an investigator of the Howard Hughes Medical Institute, and a professor of molecular biology at the University of Texas Southwestern Medical Center at Dallas. On weekends, he’s also a chauffer to violin, piano, and ice-skating lessons for his daughters, ages 11 and 9. Colleagues say Dr. Chen is scientifically fearless, with a serious-but-friendly demeanor that carries over when he challenges others to ping-pong or poker at conferences. That competitive streak paid off when Dr. Chen made a startling discovery about a new function for ubiquitin—that it could serve to actually activate some proteins instead of dooming them to the proteasome.
While working at a biotechnology company, ProScript, in Boston, Dr. Chen began investigating what role ubiquitin played in the NF-kB signaling pathway in his “spare time.” Individual cells use the NF-kB pathway to convert critical signals that occur within the cell or on its surface—signals such as when the immune system has detected the presence of a foreign invader—into a “high alert” system inside the cell’s nucleus that turns on the right combination of genes to respond appropriately.
NF-kB is a key switch in the system.When activated, NF-kB moves from the cytoplasm into the nucleus where it can turn on more than 200 genes to start specific cellular programs such as immune responses, inflammation, or cell death. In 1996, Dr. Chen,working with Tom Maniatis of Harvard University, showed that for proper NF-kB signaling, a protein kinase must be activated by ubiquitin. A kinase is an enzyme, or biochemical catalyst, that modifies other proteins in a way that changes their functional properties.
“How does ubiquitin activate a kinase? That was a very important question and it was better pursued in an academic setting,” Dr. Chen said. He moved from his company job to UT-Southwestern, in 1997, where he started his own lab to follow that question. His group soon showed that this new form of ubiquitin tagging was distinct from the tagging used for protein degradation, and moreover that the tags could be recognized by potential protein partners.
“Ubiquitin tags are like what I call a big phosphate group,” said Dr. Chen, referring to the other method cells use to activate or inhibit proteins. “It serves as a mark for other proteins to interact with the polyubiquitinated protein, to recruit other proteins into a signaling cascade.”
With his BWF award,Dr. Chen moved his research into the area of infectious disease, to look at how NF-kB plays a role in responding to RNA viruses, such as influenza, hepatitis C,West Nile, and SARS. (RNA viruses get their name because they are composed of only this particular genetic molecule.) Scientists already knew that NF-kB and other specialized proteins called transcription factors respond to viral invaders by turning on proteins called interferons. Interferons can then suppress the replication of viruses and assembly of new virus particles. But the cascade—how the signal travels from detection of viral RNA to activating NF-kB to interferons, eventually turning on genes to stop virus replication—was riddled with knowledge gaps.
“The funding from BWF was very important, because it allowed us to get into new territory for our lab,” Dr. Chen said. As a return on investment, his laboratory identified a key player in the virus-stimulated NF-kB pathway, called mitochondrial antiviral signaling, or MAVS, that sits on the mitochondrion and is required to activate NF-kB.
“What makes this exciting is that this is the first mitochondrial protein known to play a direct role in immunity,” Dr. Chen said. “Mitochondria are well known for their role in providing the energy that drives cellular reactions and for initiating a programmed cell death pathway called apoptosis. Being on the lookout for viral invaders is an altogether new function of these organelles.”
MAVS led Dr. Chen’s group to discover that some viruses, such as hepatitis C, can escape detection by the cell by clipping MAVS off the mitochondrial membrane and rendering it useless for transmitting the signal on to NF-kB. Dr. Chen said this may be why hepatitis C infections can be stubbornly persistent in about 80 percent of people infected.
Dr. Chen’s group also has shown that mice with little or no MAVS are supersusceptible to viruses, dying from infections that a normal mouse’s immune system would fight off. In collaboration with physicians, the group is trying to determine if genetic differences in the human MAVS protein might influence immunity to viruses in different people.
In the future, Dr. Chen wants to investigate whether MAVS is involved in certain autoimmune diseases, such as lupus, in which patients produce too much interferon that leads to painful, chronic inflammation. A method to inhibit MAVS might offer some relief to such patients, he said.
Dr. Chen and his colleagues also are pursuing exactly how MAVS, which is anchored to the mitochondrial membrane, stimulates the protein kinases that activate NF-kB, which reside in the cytosol, or internal fluid, of cells.“How do you signal from the mitochondria to the cytosol?” Chen said.“The ubiquitin signaling mechanism we discovered is likely to play a role here as well, and it would be a nice convergence of our two research areas.”
Article by Kendall Powell, a freelance science journalist based in Colorado.