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

Abstract

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.

Augmented genetic decoding: global, local and temporal alterations of decoding processes and codon meaning

“…Moreover, such abortive frameshifting regulated by miRNAs was reported in a human gene, the HIV-1 co-repressor CCR5 (REF. 117). …”

“…mRNA interacts with various cellular components, and these interactions may alter the stimulatory properties of particular structures or sequences. Both protein molecules 140 and nucleic acid molecules 117,141,142 have been shown to modulate frameshifting in trans. The dependence of frameshifting on stimulatory elements, as well as the responsiveness to cellular conditions, provides translation with a powerful regulatory mechanism.…”

mRNAs involved in copper homeostasis are regulated by the nonsense-mediated mRNA decay pathway depending on environmental conditions

“…e Start codon is in a suboptimal context, mRNA may be targeted to NMD through leaky scanning. of mRNA by NMD (Belew et al, 2011(Belew et al, , 2014. While PCA1 mRNA was not predicted to have a long 3 0 -UTR, 3 0 -RACE and northern analyses showed that PCA1 produces two mRNA isoforms, one with an atypically long 3 0 -UTR (Table 1).…”

“…Previous studies in S. cerevisiae have identified features that target natural mRNAs to the pathway. These features include mRNAs subject to leaky ribosomal scanning (Welch and Jacobson, 1999), a translated upstream open reading frame (uORF) (Gaba et al, 2005), À1 ribosomal frameshifts (into an alternative reading frame) (Belew et al, 2011(Belew et al, , 2014, inefficiently spliced pre-mRNAs (He et al, 1993), and mRNAs with atypically long 3 0 -untranslated regions (UTRs) (Deliz-Aguirre et al, 2011;Kebaara and Atkin, 2009;Parker, 2012;Peccarelli and Kebaara, 2014b;Rebbapragada and Lykke-Andersen, 2009;Schweingruber et al, 2013). One specific targeting mechanism of interest is the presence of a long 3 0 -UTR on an mRNA (Deliz-Aguirre et al, 2011;Kebaara and Atkin, 2009;Rebbapragada and Lykke-Andersen, 2009).…”

Mechanisms of Evolutionary Innovation Point to Genetic Control Logic as the Key Difference Between Prokaryotes and Eukaryotes

“…Short ribosomal frameshifting is found ubiquitously, with different chemistry in different domains speaking to different origins (Belew et al 2014;Brierley et al 1989;Chandler and Fayet 1993;Cobucci-Ponzano et al 2005;Dinman 2012;Lang et al 2014) RNA is also central to priming DNA synthesis at specific sites in prokaryotes and eukaryotes. However, a large number of phage and eukaryotic viral examples show that proteins can also prime DNA synthesis (Salas 1991).…”