The stop-and-go traffic regulating protein biogenesis: How translation kinetics controls proteostasis

Abstract

Generating a functional proteome requires the ribosome to carefully regulate disparate co-translational processes that determine the fate of nascent polypeptides. With protein synthesis being energetically expensive, the ribosome must balance the costs of efficiently making a protein with those of properly folding it. Emerging as a primary means of regulating this trade-off is the nonuniform rate of translation elongation that defines translation kinetics. The varying speeds with which the ribosome progresses along a transcript have been implicated in several aspects of protein biogenesis, including co-translational protein folding and translational fidelity, as well as gene expression by mediating mRNA decay and protein quality control pathways. The optimal translation kinetics required to efficiently execute these processes can be distinct. Thus, the ribosome is tasked with tightly regulating translation kinetics to balance these processes while maintaining adaptability for changing cellular conditions. In this review, we first discuss the regulatory role of translation elongation in protein biogenesis and what factors influence elongation kinetics. We then describe how changes in translation kinetics signal downstream pathways that dictate the fate of nascent polypeptides. By regulating these pathways, the kinetics of translation elongation has emerged as a critical tool for driving gene expression and maintaining proteostasis through varied mechanisms, including nascent chain folding and binding different ribosome-associated machinery. Indeed, a growing number of examples demonstrate the important role of local changes in elongation kinetics in modulating the pathophysiology of human disease.

Keywords: chaperone; cotranslational folding; elongation rate; nascent chain; protein folding; protein misfolding; ribosome function; translation; translational fidelity.

Figure 1.

Translation kinetics balances protein production, folding, and quality control pathways. Nonuniform rates of translation elongation along a transcript dictate a set of trade-offs that either enhance (blue) or diminish (orange) accurate gene expression. Slower rates of elongation enhance accurate gene expression by facilitating proper protein folding, but very slow translation (ribosome stalling) diminishes gene expression by causing the turnover of the nascent protein and mRNA. Fast translation also has its trade-offs on accurate gene expression by enhancing the fidelity and efficiency of protein synthesis, while also increasing the likelihood of protein misfolding and aggregation.

Figure 2.

Interdependent factors regulate translation kinetics and disparate downstream consequences through the recruitment of trans-acting factors. Several upstream variables dictate the speed at which the ribosome proceeds across an mRNA transcript. These determinants of translation kinetics include codon usage and tRNA abundance, which define codon optimality, along with pairs of codons (codon context), mRNA secondary structure, and protein sequence. Changes in elongation rate then modulate downstream pathways that determine the fate of nascent polypeptides. On the one hand, fast translation of protein structural elements enhances translation fidelity and translation efficiency. On the other hand, transient ribosome pausing facilitates subsequent processes by recruitment of various machinery. This includes membrane targeting of secretory proteins by recruiting the SRP after exposure of targeting signals such as a transmembrane domain (TMD), as well as protein folding possibly by recruiting molecular chaperones. Proper protein folding might then accelerate translation. When a ribosome stalls, RQC machinery is recruited to degrade the nascent polypeptide, and the DEAD-box helicase Dhh1 initiates mRNA decay.

Figure 3.

Modeling the impact of regulating translation kinetics. The kinetics of translation along an mRNA transcript is nonuniform and balanced between ribosome pausing and acceleration. In homeostatic conditions in the cell, this balance is optimized for proper folding of the nascent proteome. Deviation from this balance decreases the likelihood of folding and impacts the fate of the protein: Aberrantly fast translation leads to misfolding and aggregation, and aberrantly slow translation leads to protein and mRNA turnover. The details that define the probability distribution of protein folding will change in response to changing cellular environments. For instance, alterations in the tRNA pool will influence what codons are considered optimal versus nonoptimal, which subsequently impacts protein folding.