Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 21, Pages E2172-E2181Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1321930111
Keywords
genetic recoding; translational control; nsp1beta
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada [311775-2010]
- Wellcome Trust [088789]
- UK Biotechnology and Biological Sciences Research Council [BB/G008205/1]
- TOP Grant from the Council for Chemical Sciences of the Netherlands Organization for Scientific Research [700.57.301]
- US Department of Agriculture National Institute of Food and Agriculture [2007-01745]
- Biotechnology and Biological Sciences Research Council [BB/G008205/1, BB/L000334/1] Funding Source: researchfish
- BBSRC [BB/G008205/1, BB/L000334/1] Funding Source: UKRI
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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 (nsp1 beta). Embedded in nsp1 beta'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 nsp1 beta 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.
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