Ribosomal frameshifting in the CCR5 mRNA is regulated by miRNAs and the NMD pathway

Programmed −1 ribosomal frameshift (−1 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Although well characterized in viruses, how these elements may regulate cellular gene expression is not understood. Here we describe a −1 PRF signal in the human mRNA encoding CCR5, the HIV-1 co-receptor. CCR5 mRNA-mediated −1 PRF is directed by an mRNA pseudoknot, and is stimulated by at least two microRNAs. Mapping the mRNA–miRNA interaction suggests that formation of a triplex RNA structure stimulates −1 PRF. A −1 PRF event on the CCR5 mRNA directs translating ribosomes to a premature termination codon, destabilizing it through the nonsense-mediated mRNA decay pathway. At least one additional mRNA decay pathway is also involved. Functional −1 PRF signals that seem to be regulated by miRNAs are also demonstrated in mRNAs encoding six other cytokine receptors, suggesting a novel mode through which immune responses may be fine-tuned in mammalian cells.

• Publication year

  2014

• Venue

  Nature

• Publication date

  2014-07-09

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nature13429PMID 25043019PMCID 4369343
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2012influential reference
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  2012cited by this paper
• Programmed −1 frameshifting efficiency correlates with RNA pseudoknot conformational plasticity, not resistance to mechanical unfolding

  2012cited by this paper
• Automated 3D structure composition for large RNAs

  2012cited by this paper
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• RNA FRABASE 2.0: an advanced web-accessible database with the capacity to search the three-dimensional fragments within RNA structures

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  2009cited by this paper
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  2009cited by this paper
• RNA2D3D: A program for Generating, Viewing, and Comparing 3-Dimensional Models of RNA

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• NCBI GEO: archive for high-throughput functional genomic data

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• PRFdb: A database of computationally predicted eukaryotic programmed -1 ribosomal frameshift signals

  2008cited by this paper
• Chapter 3. Assays of adenylate uridylate-rich element-mediated mRNA decay in cells.

  2008cited by this paper
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• Solution structure and thermodynamic investigation of the HIV-1 frameshift inducing element.

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• Regulation of mRNA stability in mammalian cells.

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• Sequence evolution of the CCR5 chemokine receptor gene in primates.

  1999cited by this paper
• Research article

  1999cited by this paper
• A dual-luciferase reporter system for studying recoding signals.

  1998cited by this paper
• Release factor RF-3 GTPase activity acts in disassembly of the ribosome termination complex.

  1998cited by this paper
• Effects of CCR5 and CD4 Cell Surface Concentrations on Infections by Macrophagetropic Isolates of Human Immunodeficiency Virus Type 1

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• BIONJ: an improved version of the NJ algorithm based on a simple model of sequence data.

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  1983cited by this paper
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  1980cited by this paper

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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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