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

Programmed 21 ribosomal frameshift (21 PRF) signals redirect translating ribosomes to slip back one base on messenger RNAs. Althoughwell characterized in viruses, how these elementsmay regulate cellular gene expressionis not understood. Here we describe a 21 PRF signal in the human mRNA encoding CCR5, the HIV-1 co-receptor. CCR5 mRNA-mediated 21 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 21 PRF. A 21 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 21 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.