Defensive Proteins Prevent Infection by Recognizing and Immobilizing Viral RNA

X-ray crystallography was used to capture images of an IFIT protein while it was bound to a viral triphosphorylated RNA molecule.

IFITs are defensive proteins that go into action when the immune system determines that is facing an attack by an RNA virus. Recently it was discovered that IFITs can directly recognize viral RNA bearing a 5′-triphosphate group (PPP-RNA), which is a molecular signature that distinguishes viral RNA from that of the host.

Investigators at McGill University (Montreal, Canada) employed a battery of sophisticated analytical tools including mutational analysis, proteolysis and gel-shift assays, and X-ray crystallography to determine exactly how IFITs tie up viral RNA.

Results of these studies, which were published in the January 13, 2013, online edition of the journal Nature, revealed a new helical domain housing a positively charged cavity designed to specifically engage only single-stranded triphosphorylated RNA. PPP-RNA was bound in a nonsequence-specific manner and required a 5′-overhang of approximately three nucleotides. Blocking PPP-RNA binding to IFIT1 and IFIT5 was found to cause a defect in the antiviral response by human embryonic kidney cells.

"Infection by pathogens such as viruses and bacteria are caught by a layer of the immune system that consists of guard-like proteins constantly on the lookout for foreign molecules derived from the pathogen," said senior author Dr. Bhushan Nagar, professor of biochemistry at McGill University. "Once the pathogen is detected, a rapid response by the host cell is elicited, which includes the production of an array of defender molecules that work together to block and remove the infection. The IFIT proteins are key members of these defender molecules."

"Our findings will be useful for the development of novel drugs directed at IFIT proteins, particularly in cases where it is necessary to dampen the immune response, such as inflammation or cancer therapy," said Dr. Nagar.

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