Sexual HealthViruses Are Sneakier Than We Thought
Viruses are molecular marauders, plundering cells for the res they
need to multiply. Of central importance for viruses is the ability to
commandeer cellular gene expression machinery. Several human
herpesviruses put the breaks on normal cellular gene expression to divert
the associated
enzymes and res towards their own viral genes. Kaposi"s
sarcoma-associated herpesvirus (KSHV), which causes several
AIDS-associated cancers,
has now been shown to do this in an unexpected way, using a process that
is normally protective, called polyadenylation.
Cells decode genetic information in a process called transcription, during
which the DNA is unzipped and read by enzymes. The product of this process
is a piece of messenger RNA, which then emerges from the cell"s nucleus
(the section of the cell containing DNA) into the cell cytoplasm (the main
cellular compartment) and is translated there into the protein
corresponding to the DNA"s message. Polyadenylation is the process
whereby Poly(A)
tails are added to messenger RNAs (mRNAs) in the nucleus before they are
transported into the cytoplasm. These tails serve several purposes,
including
protecting the messages from degradation and enhancing the translation to
protein. The effects of KSHV on cells was known to be caused by one of
it"s proteins - called SOX - but how the protein influences host cells
transcription process has previously been unclear.
In a study published in this week"s issue of PLoS Biology, researchers at
UC Berkeley found that the presence of SOX led to an unexpected increase
in the length of cellular mRNA poly(A) tails. Mutant KSHV viruses that can"t
make SOX protein are unable to block cellular gene expression. SOX
mutants fail to increase poly(A) tail length. This suggests that the virus
uses a process normally involved in enhancement of gene expression to
instead inhibit gene expression.
"We suspect that by aberrantly lengthening the poly(A) tails, the virus is
sending the cell a signal that something is wrong with its messages and
as a consequence they are held back in the nucleus," says Dr. Britt
Glaunsinger, one of the researchers involved in this study. Indeed,
similar
results have been observed in yeast when mRNAs are improperly made or
cannot traffic appropriately.
The researchers showed that SOX has more than one trick to play on cells -
as well as preventing the export of new cellular mRNAs, SOX targets the
existing messages that were made in a cell before the KSHV could turn on
its SOX protein. mRNA poly(A) tails are normally bound by the cell"s
poly(A) binding protein (PABP), which helps guard them from degradation
and facilitates their translation into protein. During KSHV infection,
however, SOX removes PABP from the cytoplasm and causes it to instead
accumulate in the nucleus. PABP re-localization correlates with
destruction of
cytoplasmic mRNA in SOX-expressing cells, perhaps because these
transcripts have been "stripped" of an important protector. "I find it
fascinating that this single viral protein targets a key mRNA stabilizing
element from two different angles to block cellular gene expression," says
Glaunsinger. "It"s yet another example of how viruses have evolved to
interface so exquisitely with their hosts."
Funding: This research was supported by a Howard Temin Career Development
Award and a Burroughs Wellcome Fund Investigators in the Pathogenesis of
Infectious Disease Award to BG. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the
manuscript.
Competing interests statement: The authors declare that no competing
interests exist.
Citation:
"Aberrant Herpesvirus-Induced Polyadenylation Correlates With Cellular Messenger RNA Destruction."
Lee YJ, Glaunsinger BA (2009)
PLoS Biol 7(5):e1000107.
Plos Biology