A deterministic model for non-monotone relationship between translation of upstream and downstream open reading frames

Abstract

Totally asymmetric simple exclusion process (TASEP) modelling was shown to offer a parsimonious explanation for the experimentally confirmed ability of a single upstream open reading frames (uORFs) to upregulate downstream translation during the integrated stress response. As revealed by numerical simulations, the model predicts that reducing the density of scanning ribosomes upstream of certain uORFs increases the flow of ribosomes downstream. To gain a better insight into the mechanism which ensures the non-monotone relation between the upstream and downstream flows, in this work, we propose a phenomenological deterministic model approximating the TASEP model of the translation process. We establish the existence of a stationary solution featuring the decreasing density along the uORF for the deterministic model. Further, we find an explicit non-monotone relation between the upstream ribosome density and the downstream flow for the stationary solution in the limit of increasing uORF length and increasingly leaky initiation. The stationary distribution of the TASEP model, the stationary solution of the deterministic model and the explicit limit are compared numerically.

Ghrelin rapidly elevates protein synthesis in vitro by employing the rpS6K-eEF2K-eEF2 signalling axis

“…Phosphorylation of eEF2 results in slowing elongation while has no known direct effect on scanning ribosomes. Therefore, it will likely affect the progression of leaky scanning ribosomes through the translated uORFs [ 64 , 65 ]; this would have different impact on initiation at protein coding regions depending on the properties of uORFs in their 5' leaders. In addition, slowed elongation can promote initiation at suboptimal start codons, especially at non-AUG initiation codons such as CUG and GUG [ 63 , 66 ].…”