Scientists reveal a new way to cause viruses
cells to self-destruct
Brookhaven National Laboratory Press
- Tuesday, 19 November 2002
"This is a new and philosophically interesting way for a
virus to escape from cells," said Brookhaven biologist Walter Mangel, a co-author on the paper. "In essence, a
protein in the infected cells can serve as the seed of the cells' own
Mangel's group has previously shown that adenovirus -- a virus that causes
respiratory and gastrointestinal infections and also conjunctivitis --
produces a protein-cleaving enzyme, or protease, to complete the maturation
of newly synthesized virus particles. Similar to the way supportive
scaffolding is removed after the completion of a construction project, this
protease cleaves, or cuts out, viral "construction" proteins, leaving
infectious virus particles behind.
This viral protease is produced in the cytoplasm in an inactive form, and
must migrate to the nucleus to become activated in newly synthesized viral
particles by two viral cofactors. Once activated, it can cleave several
viral proteins to complete the viral maturation process. There were no
indications that the protease could be activated in the cellšs cytoplasm.
When Mangel presented this research at a seminar at Princeton University,
Clarence Schutt, a Princeton chemistry professor, pointed out that the amino
acid sequence of one of the viral cofactors was dramatically similar to the
sequence of actin, a cytoplasmic protein that gives shape and structure to
cells. Mangel wondered if actin could activate the protease, and took some
from Schutt's lab back to Brookhaven to do the experiment.
Scientists at the U.S. Department of Energy's Brookhaven National Laboratory
and their collaborators have discovered that some viruses can use the most
abundant protein in the cells they are infecting to destroy the cells and
allow new viruses to escape to infect others. The findings, described in the
November 29, 2002, issue of the Journal of Biological Chemistry, build upon
earlier Brookhaven research on how virus particles become infectious and may
lead to the design of more effective antiviral remedies.
The result: Incubating actin and the adenovirus protease increased the
cleaving ability of the protease, just like the viral cofactor did, allowing
the actin-protease complex to cleave actin itself, as well as other cellular
"When actin and other cytoskeleton proteins are destroyed," Mangel
explained, "a cell loses its shape and eventually breaks open, allowing the
newly synthesized virus particles to escape and infect other cells."
While other viruses are known to cleave actin and other cytoskeleton
proteins as a means of breaking free to continue infection, none of them is
known to use actin as a cofactor in this process, Mangel said. "Thus, the
really interesting finding in this case is that actin is a cofactor for its
own destruction," Mangel said.
The next step for Mangel's group will be to crystallize complexes of actin
bound to the adenovirus protease to determine its atomic structure at the
National Synchrotron Light Source at Brookhaven.
"The structure would then be used to find drugs to prevent the interaction
between actin and the adenovirus protease," Mangel said. "Such drugs could
serve as a new type of antiviral agent."
This work was done in collaboration with Mark Brown, Kevin McBride, Mary
Lynn Baniecki, and Nancy Reich of Stony Brook University and Gerard Marriott
of the University of Wisconsin. It was funded by the U.S. Department of
Energy, which supports basic research in a variety of scientific fields, and
the National Institutes of Health.
Brookhaven National Laboratory Press Release