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

Nature. 2014 Aug 21;512(7514):265-9. doi: 10.1038/nature13429. Epub 2014 Jul 9.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Binding Sites
  • Cell Survival
  • Codon, Nonsense / genetics
  • Frameshifting, Ribosomal / genetics*
  • HeLa Cells
  • Humans
  • MicroRNAs / genetics*
  • Models, Molecular
  • Molecular Sequence Data
  • Nonsense Mediated mRNA Decay*
  • Nucleic Acid Conformation
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism*
  • Receptors, CCR5 / genetics*
  • Receptors, Interleukin / genetics
  • Regulatory Sequences, Ribonucleic Acid
  • Ribosomes / metabolism


  • Codon, Nonsense
  • MicroRNAs
  • RNA, Messenger
  • Receptors, CCR5
  • Receptors, Interleukin
  • Regulatory Sequences, Ribonucleic Acid