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Discovered a new gene expression mechanism in porcine reproductive and respiratory syndrome

These studies demonstrate for the first time, to our knowledge, that a protein can function as a transactivator of ribosomal frameshifting.

21 May 2014
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A collaborative study involving Kansas State University researchers has discovered a new gene expression mechanism in porcine reproductive and respiratory syndrome, or PRRS, virus — an important swine pathogen that costs the U.S. pork industry more than $600 million a year. The discovery provides a new avenue for scientists to explore strategies to control and prevent the disease.

Ying Fang, Ph.D., associate professor of diagnostic medicine and pathobiology at Kansas State University, led a study that looked at the unique gene expression mechanism of the PRRS virus. She and colleagues found a new protein in the virus, nsp2TF, was generated through novel ribosomal frameshifting signals. Fang conducted this study with her European collaborators, including Eric Snijder and his team members at Leiden University Medical Center in The Netherlands, and Andrew Firth, Ian Brierley and Brierley's lab members at the University of Cambridge.

Programmed −1 ribosomal frameshifting (−1 PRF) is a widely used translational mechanism facilitating the expression of two polypeptides from a single mRNA. Commonly, the ribosome interacts with an mRNA secondary structure that promotes −1 frameshifting on a homopolymeric slippery sequence. Recently, we described an unusual −2 frameshifting (−2 PRF) signal directing efficient expression of a transframe protein [nonstructural protein 2TF (nsp2TF)] of porcine reproductive and respiratory syndrome virus (PRRSV) from an alternative reading frame overlapping the viral replicase gene. Unusually, this arterivirus PRF signal lacks an obvious stimulatory RNA secondary structure, but as confirmed here, can also direct the occurrence of −1 PRF, yielding a third, truncated nsp2 variant named “nsp2N.” Remarkably, we now show that both −2 and −1 PRF are transactivated by a protein factor, specifically a PRRSV replicase subunit (nsp1β). Embedded in nsp1β’s papain-like autoproteinase domain, we identified a highly conserved, putative RNA-binding motif that is critical for PRF transactivation. The minimal RNA sequence required for PRF was mapped within a 34-nt region that includes the slippery sequence and a downstream conserved CCCANCUCC motif. Interaction of nsp1β with the PRF signal was demonstrated in pull-down assays.

These studies demonstrate for the first time, to our knowledge, that a protein can function as a transactivator of ribosomal frameshifting. The newly identified frameshifting determinants provide potential antiviral targets for arterivirus disease control and prevention. Moreover, protein-induced transactivation of frameshifting may be a widely used mechanism, potentially including previously undiscovered viral strategies to regulate viral gene expression and/or modulate host cell translation upon infection.

Yanhua Li, Emmely E. Treffers, Sawsan Napthine, Ali Tas, Longchao Zhu, Zhi Sun, Susanne Bell, Brian L. Mark, Peter A. van Veelen, Martijn J. van Hemert, Andrew E. Firth, Ian Brierley, Eric J. Snijder and Ying Fang.Transactivation of programmed ribosomal frameshifting by a viral protein. Proceedings of the National Academy of Sciences of the United States of America. doi: 10.1073/pnas.1321930111

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