Understanding the regulation of protein synthesis under stress conditions.

Protein synthesis regulation primarily occurs at translation initiation, the first step of gene translation. However, the regulation of translation initiation under various conditions is not fully understood. Specifically, the reason why protein production from certain mRNAs remains resistant to stress while others do not show such resilience. Moreover, why is protein production enhanced from a few transcripts under stress conditions, whereas it is decreased in the majority of transcripts? We address them by developing a Monte Carlo simulation model of protein synthesis and ribosome scanning. We find that mRNAs with strong Kozak contexts exhibit minimal reduction in translation initiation rate under stress conditions. Moreover, these transcripts exhibit even greater resilience to stress when the scanning speed of 43S ribosome subunit is slow, albeit at the cost of reduced initiation rate. This implies a trade-off between initiation rate and the ability of mRNA to withstand stress. We also show that mRNAs featuring an upstream ORF can act as a regulatory switch. This switch elevates protein production from the main ORF under stress conditions; however, minimal to no proteins are produced under the normal condition. Because, in stress, a larger fraction of 43S ribosomes bypasses the upstream ORF due to its weak Kozak context. This, in turn, increases the number of scanning ribosomes reaching the main ORF, whose strong Kozak context can convert them into 80S ribosomes, even under stress conditions. This switching allows an efficient use of cellular resources by producing proteins when they are required. Thus, our computational study provides valuable insights into our understanding of stress-responsive translation-initiation.