COLUMBUS, Ohio – Researchers unraveling the biochemistry of a cancer-causing retrovirus here have found a protein produced by the virus that has an uncanny resemblance to a key cell protein found in certain immune cells that helps control calcium signaling.
The scientists believe that HTLV-1 (human T-lymphotrophic virus-1) uses its protein called p12 to help change these immune cells from a normal resting state to an active state, thereby speeding up cell division which, in turn, replicates the virus.
If confirmed, the finding could provide valuable insight into just how retroviruses overwhelm the human immune system. The study is reported in the current issue of the Journal of Biological Chemistry.
The trail leading to this finding began with some little-understood pieces of the HTLV-1 genome. Viruses often have specific genes that produce specific proteins that start, stop or regulate processes in the cell to allow the virus to reproduce.
The researchers here focused on one particular motif, or portion of the protein p12, that contains an amino acid sequence similar to a well-known cell protein called Nuclear Factor of Activated T-cells, of NFAT. Their earlier research had proved that in animals where the virus lacked the gene that makes p12 -– the HTLV-1 virus couldn't reproduce.
"We found that that gene was needed for the virus to replicate – not in cell cultures but in whole animals," explained Michael Lairmore, professor and chair of veterinary biosciences at Ohio State University. "That was important since it was the first time anyone had seen this effect after removing that gene."
Seung-jae Kim, a graduate student in Lairmore's lab and first author on the journal paper, began comparing the structure of p12 with the millions of combinations stored in the computerized human genome library.
Lairmore said the computer searches uncovered a match of a key portion of NFAT, which controls its binding to calcineurin, a key enzyme that regulates calcium signals in T-cells. The viral motif had nearly the same amino acid sequence as NFAT. In addition, both the viral protein and NFAT bound to calcineurin.
"NFAT is a transcription factor that plays a critical role in all cells by binding to the enzyme calcineurin," Lairmore said. "Once bound, it removes a phosphate group from the enzyme allowing it to travel from the cell's cytoplasm into the nucleus. Once there, the cell becomes activated and begins the process of replication."
Discovering that viral p12 plays a similar role to NFAT surprised the researchers. They realized that p12 also mimics other cell proteins' ability to allow calcium to leak out of the cell's endoplasmic reticulum, an organelle known to be a major storehouse for the element.
Calcium plays a major role in cellular processes, turning on genes that drive cellular division, among other roles. But it also has to be regulated very tightly within the cell, Lairmore said. Too much calcium and the cell dies.
Finding the binding site where p12 connects with the enzyme calcineurin was important, Lairmore said. "The calcineurin binding site has been found in everything from common yeast to African swine fever virus but this is the first time it has been found in a retrovirus."
The discovery of the similar calcineurin binding sites in NFAT and the viral protein might seem to suggest a new potential approach at thwarting the virus. Blocking the binding site could halt the calcium release which could stop cell replication. But doing so, Lairmore said, could be toxic to the cell as well as to the virus.
"Instead of offering a new anti-viral approach, this discovery may help us explain just how HTLV-1 turns these cells on, leading to cell replication," he said.
HTLV-1 is the viral cause of adult T-cell lymphoma, as well as at least two forms of neurologic disease. In many ways, it starts a cascade of processes that lead to an autoimmune disease-like state. These are chronic and usually fatal illnesses.
Exposure to HTLV-1 can lead to infection in 60 percent of the people who may encounter it from blood transfusions that might not have been tested for the virus. Since 1988, the United Stares' blood supply has been screened to prevent HTLV-1 transmission.
About 5 percent of infected people will develop disease, while the remaining 95 percent become carriers. However, decades can pass between the initial infection and when a patient develops a disease, if it does arise at all.
This research was supported by both the National Institutes of Health and the National Cancer Institute. Along with Kim and Lairmore, Ohio State researchers Wei Ding and Bjorn Albrecht, and Patrick Green, now with the Howard Hughes Medical Institute, all contributed to the research.
Materials provided by Ohio State University. Note: Content may be edited for style and length.
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