TASEP modelling provides a parsimonious explanation for the ability of a single uORF to upregulate downstream ORF translation during the Integrated Stress Response

Abstract

Translation initiation is the rate limiting step of protein synthesis that is downregulated during Integrated Stress Response (ISR). In our previous work (Andreev, OConnor et al 2015), we demonstrated that most human mRNAs resistant to this inhibition possess translated uORFs and in some cases a single uORF is sufficient for the resistance. Here we developed a computational model of Initiation Complexes Interference with Elongating Ribosomes (ICIER) to gain insight into the mechanism. We explored the relationship between the flux of scanning ribosomes upstream and downstream of a single uORF depending on uORF features. Paradoxically our analysis predicts that reducing ribosome flux upstream of certain uORFs increases initiation downstream. The model reveals derepression of downstream translation as general mechanism of uORF-mediated stress resistance. It predicts that stress resistance can be achieved with long or slowly translated uORFs that do not favor high levels of translation re-initiation and start with non-leaky initiators.