Manipulation of ribosomes by viral RNAs

Abstract

Viruses employ a variety of strategies to manipulate the basic molecular machinery of their hosts and to coordinate important events during infection. In many cases, virally encoded RNAs are at the heart of these strategies. One example of this are in viral internal ribosome entry sites (IRES) RNAs, which recruit, position, and activate the host cell's translation machinery to the viral RNA. The correct functioning of IRESs is critical for the successful infection of these viruses, which include hepatitis C virus, polio, HIV‐1, and others. In addition, IRESs are used by some cellular mRNAs and are thus are a potentially important mechanism of post‐transcriptional gene regulation. The intergenic region (IGR) IRESs of the Dicistroviridae viruses use the most streamlined IRES mechanism identified to date, binding directly to the ribosome and manipulating it into initiating translation of the viral message. As such, the IGR IRESs have been dubbed “molecular hijackers.” We are using the IGR IRESs as a model to understand some of the basic molecular tenets of IRES RNA structure, IRES‐ribosome interactions and IRES function, as well as to understand the basic workings of the ribosome that are potentially important for post‐transcription regulation, in general. We have developed a detailed model for the mechanism of the IGR IRESs using results from cryo‐EM, X‐ray crystallography, and other structural, functional, and biophysical methods. I will present new data from both structural and functional studies that test our mechanistic model and also suggest new ideas for how these RNA‐based molecular hijackers work.