Function and origin of mistranslation in distinct cellular contexts

Abstract

Mistranslation describes errors during protein synthesis that prevent the amino acid sequences specified in the genetic code from being reflected within proteins. For a long time, mistranslation has largely been considered an aberrant cellular process that cells actively avoid at all times. However, recent evidence has demonstrated that cells from all three domains of life not only tolerate certain levels and forms of mistranslation, but actively induce mistranslation under certain circumstances. To this end, dedicated biological mechanisms have recently been found to reduce translational fidelity, which indicates that mistranslation is not exclusively an erroneous process and can even benefit cells in particular cellular contexts. There currently exists a spectrum of mistranslational processes that differ not only in their origins, but also in their molecular and cellular effects. These findings suggest that the optimal degree of translational fidelity largely depends on a specific cellular context. This review aims to conceptualize the basis and functional consequence of the diverse types of mistranslation that have been described so far.

Keywords: Mistranslation; adaptation; misacylation; miscoding; ribosome; stress response; tRNA.

Figure 1. Cellular processes engendering mistranslation

Mistranslation can result from any of the processes that mediate the flow of information from DNA to proteins.

Figure 2. Naturally ambiguous translation

(A) Ambiguous translation in Mycoplasma species results from lost or inactive editing sites in several tRNA synthetases that allow noncognate amino acids to be charged to tRNAs. (B) Ambiguous translation occurs in Candida species due to tRNA^SerCAG being recognized by both SerRS and LeuRS and resulting in CUG codons being translated as both Ser and Leu. (C) Ambiguous translation in Mycobacteria results from an indirect tRNA^Asn and tRNA^Gln synthesis that requires mischarged tRNA intermediates, which can be used in translation. Mutations in the GatCAB complex, which generates correctly acylated tRNA^Asn and tRNA^Gln from the mischarged tRNA intermediates, increases Asn-to-Asp and Gln-to-Glu mistranslation.

Figure 3. MetRS mechanisms mediating the conditional acceptance of noncognate tRNAs

In humans, the unmodified MetRS has high specificity, but phosphorylation at two serine residues decreases the fidelity of the enzyme allowing it to charge noncognate tRNAs. In A. pernix, the MetRS is capable of undergoing a temperature dependent decrease in fidelity to specifically accept tRNA^Leu at lower physiological temperatures. In E. coli, the unmodified MetRS has low specificity and accepts noncognate tRNAs; a succinyllysine modification is required to impart high-tRNA charging fidelity. This modification is removed when Met mistranslation is induced in vivo.

Figure 4. General effect of regulated and unregulated mistranslation on protein activity

High fidelity translation produces a homogenous protein population that shares identical activity optima for all cellular conditions. Regulated mistranslation allows amino acid substitutions and their frequency to be controlled. This enables proteins to maintain their structures while diversifying their activities. The blue region in the graph indicates nonoptimal conditions where mistranslated proteins may have higher activity than their wild-type counterparts. Unregulated mistranslation can result in discordant amino acid substitutions that prevent proper protein folding resulting in protein inactivity.

Figure 5. Specific roles for mistranslation

Mistranslation can have benefits independent of the direct effects of substituting amino acids within proteins such as expediting/maintaining translation during amino acid limitation and activating transcriptional stress responses (blue). Substituting amino acids within proteins can result in novel protein phenotypes that have shown to be beneficial in several ways (green). An increase in Met residues within proteins can aid the oxidative stress response in mammalian cells, likely by protecting proteins from oxidative inactivation. Mistranslation can render proteins resistant to a specific inactivating agent like rifampicin in bacteria. Mistranslation can alter a specific protein property such as rigidity to increase function in lower temperatures in archaea. Lastly, mistranslation can mediate variability of surface proteins to aid evasion of immune responses in pathogens.