In the early 1990s, as a postdoctoral fellow at the National Cancer Institute and Harvard Medical School, Jon Huibregtse was part of the team that determined how human papillomaviruses (HPVs) promote the development of cervical cancer.
It was an important biomedical breakthrough, one that helped lead to the development of a vaccine for HPV, which infects about 20 million people in America (with more than 5 million new infections contracted every year). It was also a leap forward in the basic scientific understanding of how the virus affects human cells.
“We figured out that one of the HPV proteins hijacks a key regulatory system in cervical epithelial cells,” Huibregtse said. “This results in the degradation of an important tumor suppressor, which is a key event in the development of these cancers.”
For Huibregtse, now a professor of molecular genetics and microbiology, that discovery was the beginning of a more than decade-long investigation of a class of proteins, known as ubiquitin ligases, that play a central role in regulating the life of a cell.
“The ubiquitin system is found in every cell in every eukaryotic organism,” Huibregtse said. “It is, as the name suggests, ubiquitous. It functions as a specific tag to eliminate proteins from the cell.”
When ubiquitin ligases are working properly, Huibregtse said, they signal that certain other proteins, which have completed their tasks, should be destroyed. The result is that no-longer-useful proteins are directed into the proteosome, the cell’s “garbage disposal.” The proteosome breaks the old proteins apart and releases the pieces to be recycled into new proteins.
When ubiquitin ligases are reprogrammed or inhibited, however, the results can be disastrous. For example, a brain-specific loss in the production of the ligase that was discovered in the course of Huibregtse’s HPV research leads to the severe neurologic disease called Angelman Syndrome.
In the case of HPVs, the virus reprograms this ligase to tag a protein called p53, Huibregtse said, which is “so important to protecting cells from mutations that it’s been dubbed the guardian of the genome.” With the p53 tumor suppressor protein destroyed, the likelihood of cancer development increases dramatically.
“But remember,” Huibregtse said, “the HPVs have no interest in causing cancer; they are just trying to get by — to propagate themselves. In fact, the specific molecular events that lead to cervical cancer ensure that the virus will no longer replicate. From the perspective of both the virus and the host, the consequence of the initial viral infection can, quite literally, be a dead-end.”