Autoregulatory systems controlling translation factor expression: thermostat-like control of translational accuracy

Abstract

In both prokaryotes and eukaryotes, the expression of a large number of genes is controlled by negative feedback, in some cases operating at the level of translation of the mRNA transcript. Of particular interest are those cases where the proteins concerned have cell-wide function in recognizing a particular codon or RNA sequence. Examples include the bacterial translation termination release factor RF2, initiation factor IF3, and eukaryote poly(A) binding protein. The regulatory loops that control their synthesis establish a negative feedback control mechanism based upon that protein's RNA sequence recognition function in translation (for example, stop codon recognition) without compromising the accurate recognition of that codon, or sequence during general, cell-wide translation. Here, the bacterial release factor RF2 and initiation factor IF3 negative feedback loops are reviewed and compared with similar negative feedback loops that regulate the levels of the eukaryote release factor, eRF1, established artificially by mutation. The control properties of such negative feedback loops are discussed as well as their evolution. The role of negative feedback to control translation factor expression is considered in the context of a growing body of evidence that both IF3 and RF2 can play a role in stimulating stalled ribosomes to abandon translation in response to amino acid starvation. Here, we make the case that negative feedback control serves primarily to limit the overexpression of these translation factors, preventing the loss of fitness resulting from an unregulated increase in the frequency of ribosome drop-off.

FIGURE 1.

Translation of RF2 expression is autogenously controlled via a negative feedback loop. (A) The nucleotide sequence of the mRNA frameshift site, showing the ORF1 UGA stop codon (bold), with a 3′ C residue, the UAU E-site codon, the internal Shine–Dalgarno (SD) sequence, and its predicted base-pairing to the 16S rRNA. The structure of the RF2 gene shows the second ORF in the +1 frame relative to ORF1. (B) The frameshift mechanism is in part triggered by a leucyl tRNA wobble base paired in the ribosomal P-site. This unstable codon–anticodon interaction is one of the factors stimulating +1 frameshifting, along with a poor context UGA stop codon terminating ORF1, and a SD sequence within ORF1 that stimulates the +1 nucleotide shift.

FIGURE 2.

Translation of IF3 is autogenously controlled via a negative feedback loop acting at the level of initiation codon detection. (A) In vitro evidence suggests IF3 catalyzes continuous eviction of tRNA from the ribosomal P-site (Antoun et al. 2006). This ejection mechanism is faster if the initiator tRNA is noncognate for the initiation codon being used. For this reason, in the presence of IF3, initiation on the IF3 mRNA is highly inefficient due to the use of an AUU initiation codon. In the absence of IF3, initiator tRNA is not ejected, and IF3 translation is begun. (B) Some studies indicate a model where IF3 selectively prevents 70S formation if a noncognate P-site interaction is encountered (Grigoriadou et al. 2007). In the absence of IF3, 70S formation is not sensitive to initiator tRNA decoding fidelity, thus initiation at the infC (IF3) AUU codon is permitted.