More than a machine: Ribosome regulates viral protein synthesis, revealing potential therapeutic target

Nov 20, 2012

Viruses can be elusive quarry. RNA viruses are particularly adept at defeating antiviral drugs because they are so inaccurate in making copies of themselves. With at least one error in every genome they copy, viral genomes are moving targets for antiviral drugs, creating resistant mutants as they multiply. In the best-known example of success against retroviruses, it takes multiple-drug cocktails to corner HIV and narrow its escape route.

Rather than target themselves, aiming at the host cells they invade could hold promise, but any such strategy would have to be harmless to the host. Now, a surprising discovery made in ribosomes may point the way to fighting fatal viral infections such as rabies.

Results were published online November 19 in .

The has traditionally been viewed as the cell's molecular machine, automatically chugging along, synthesizing proteins the cell needs to carry out the functions of life. But Amy Lee, a former graduate student in the program of virology, and Sean Whelan, HMS professor of microbiology and immunobiology, now say the ribosome appears to take a more active role, regulating the translation of specific proteins and ultimately how some viruses replicate.

The researchers were studying differences between how viruses and the host cells they infect carry out the process of translating messenger RNAs (mRNAs) into proteins. Focusing on found on the surface of the ribosome, they discovered a protein that some viruses depend on to make other proteins, but that the vast majority of cellular mRNAs do not need.

Called rpL40, this could represent a target for potential treatments; blocking it would disable certain viruses while leaving normal cells largely unaffected.

"Because certain viruses are very sensitive to the presence and absence of these ribosomal proteins, it might be a useful way for us to think about targeting ribosomes for therapeutic purposes from an antiviral standpoint," said Whelan. "This is a way to think about interfering with rabies virus infection. There are no therapeutics for rabies infection."

The team screened protein constituents of the ribosome to see which ones might be involved in specialized protein synthesis. Studying the vesicular stomatitis virus, a rhabdovirus in the same family as the rabies virus, they found that its mRNAs depended on rpL40 but only 7 percent of host-cellular mRNAs did. Some of the cellular mRNAs that depend upon rpL40 were stress response genes.

Experiments in yeast and human cells revealed that a class of viruses, which includes rabies and measles, depended on rpL40 for replication.

"This work reveals that the ribosome is not just an automatic molecular machine but instead also acts as a translational regulator," said first author Amy Lee, who is now a post-doctoral researcher at the University of California, Berkeley.

The concept of targeting cellular functions such as protein synthesis for antiviral therapies is being explored by a number of research groups, but there are no drugs based on this.

"We think the principle is bigger than just this single protein," Whelan said. "Viruses have an uncanny way of teaching us new biology all the time."

Explore further: Researchers produce first atlas of airborne microbes across United States

Related Stories

Cracking a virus protection shield

Jun 16, 2006

Ebola, measles and rabies are serious threats to public health in developing countries. Despite different symptoms all of the diseases are caused by the same class of viruses that unlike most other living beings carry their ...

The silence of the genes

Apr 22, 2010

Viruses have evolved a broad range of strategies that enable them to evade the immune systems of their hosts. A team of researchers led by LMU virologist Professor Jürgen Haas has been studying a novel, recently discovered ...

Recommended for you

Viral proteins may regulate human embryonic development

2 hours ago

A fertilized human egg may seem like the ultimate blank slate. But within days of fertilization, the growing mass of cells activates not only human genes but also viral DNA lingering in the human genome from ...

Vascular cells can fuse with themselves

Apr 20, 2015

Cells of the vascular system of vertebrates can fuse with themselves. This process, which occurs when a blood vessel is no longer necessary and pruned, has now been described on the cellular level by Prof. ...

Key element in bacterial immune system discovered

Apr 20, 2015

A University of Otago scientist is a member of an international research team that has made an important discovery about the workings of a bacterial immune system. The finding could lead to the development ...

User comments : 2

Adjust slider to filter visible comments by rank

Display comments: newest first

Urgelt
not rated yet Nov 20, 2012
*Only* 7 per cent of host-cellular mRNAs rely on rpl40?

Sounds like a big number, then.

And they'll have to make sure that every single one of them is nonessential and harmless to block, if rpl40 is to be shut down by a drug.

Good luck with that.
Torbjorn_Larsson_OM
not rated yet Nov 22, 2012
This may be very neat. We know that early life was RNA/protein based, and we suspect that at least dsDNA viruses descended from the later dsDNA/protein universal ancestor. ["Giant viruses coexisted with the cellular ancestors and represent a distinct supergroup along with superkingdoms Archaea, Bacteria and Eukarya", Nasir et al, BMC Evolutionary Biology 2012.]

Similarly one can hypothesize that other virus clades have root protein functions, which have been lost in other clades. This ssRNA virus translation initiation pathway, which is a minor pathway in today's cells, may show that early ribosome functionality included protein translation regulation. A regulation later to be evolved centered on the DNA genome.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.