Writing in the May 9 issue of Science, researchers from the University of Wisconsin-Madison and Harvard Medical School report that a viral protein, called UL97, masquerades as a normal regulatory enzyme to modify a tumor-suppressing protein in human cells. Unlike the normal enzyme, which can be switched on and off by the cell as needed, the viral stand-in lacks an off switch and evades cellular control. The findings represent a previously unknown way that viruses can cause uncontrolled cell growth and division.
Cells normally have tight regulatory mechanisms in place to limit multiplication to appropriate situations, such as replacing worn-out cells or repairing damage. Uncontrolled cell proliferation can lead to cancer and other disorders.
One of the most important cellular control mechanisms works through a protein called the retinoblastoma tumor suppressor protein, which slows cell growth.
"The retinoblastoma pathway is like the brakes on a car. It prevents tumor cells from growing out of control," says Robert Kalejta, an assistant professor in the UW-Madison Institute for Molecular Virology and McArdle Laboratory for Cancer Research, who led the new study. "This pathway is mutated in essentially all human cancers."
Disrupting this pathway is also advantageous for viruses. Unable to reproduce on their own, viruses rely on co-opting their host's cellular machinery, like an occupying army taking over a local factory. They are especially good at overriding or bypassing built-in control mechanisms, Kalejta says.
"Viruses are well known to encode proteins that have similar activities to cellular proteins, but they're just different enough that they're beneficial to the virus," he says. "[UL97] shares the same activities as the cellular protein, but it lacks all of the control mechanisms."
In essence, UL97 disables the brakes and hits the gas. Once a host cell is primed toward growth, HCMV takes over and steals the cell's machinery to reproduce itself.
The virus's bloodhound-like ability to seek out and target the most essential pieces of a cell's machinery makes it a valuable research tool, Kalejta says.
"Viruses are smarter than we are. They know a lot more about cells than we do, because their life depends on it - they're obligate intracellular parasites," he says. "If they attack a part of the cell - a process or a protein - you know it's important for the cell. If the virus pays attention to it, you should too."
Kalejta next hopes to use UL97 to find other proteins that may be important for cell growth. He also sees potential clinical applications down the road. HCMV infection is very common and, though it remains asymptomatic in most people, it has been implicated in some cancers and can cause trouble in people with compromised or suppressed immune systems, such as AIDS patients and transplant recipients. In addition, UL97-like proteins are also found in the other seven human herpes viruses, some of which are directly linked to cancers.
The advantages of the research are two-fold, Kalejta says. "We're studying a virus that causes human disease and might eventually find a way to treat that infection and help patients. At the same time, we're learning about how the cell works, which has implications for patients that don't have infections," he says. "You get two for the price of one."
Other authors on the paper include Adam Hume, Jonathan Finkel, and Michael Culbertson from UW-Madison and Jeremy Kamil and Donald Coen from Harvard Medical School. The work was funded by grants from the National Institutes of Health, the Wisconsin Partnership for a Healthy Future, the Burroughs Wellcome Fund, and the American Heart Association.