Innate Immune Response Illuminated by New Study of RIG-I

When a thief breaks into a bank vault, sensors are activated and the alarm is raised. Cells have their own early-warning system for intruders, and scientists at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, have discovered how a particular protein sounds that alarm when it detects invading viruses. The study, published in the October 14, 2011 issue of Cell, is a key development in our understanding of the innate immune response, shedding light on how cells rapidly respond to a wide range of viruses including influenza, rabies, and hepatitis. To sense invading agents, cells use proteins called pattern recognition receptors, which recognize and bind to molecular signatures carried only by the intruder. This binding causes the receptors to change shape, starting a chain-reaction that ultimately alerts the surrounding cells to the invasion. How these two processes ¬– sensing and signalling – are connected, has until now remained unclear. The EMBL scientists have now discovered the precise structural mechanism by which one of these receptors, RIG-I, converts a change of shape into a signal. “For a structural biologist, this is a classic question: how does ligand binding to a receptor induce signalling?” says Dr. Stephen Cusack, who led the work. “We were particularly interested in answering it for RIG-I, as it targets practically all RNA viruses, including influenza, measles, and hepatitis C.” In response to a viral infection, RIG-I recognizes viral genetic material – specifically, viral RNA – and primes the cell to produce the key anti-viral molecule, interferon. Interferon is secreted and picked up by surrounding cells, causing them to turn on hundreds of genes that act to combat the infection.
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