TY - JOUR TI - TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response AU - Andreev, Dmitry E AU - Arnold, Maxim AU - Kiniry, Stephen J AU - Loughran, Gary AU - Michel, Audrey M AU - Rachinskii, Dmitrii AU - Baranov, Pavel V A2 - Sonenberg, Nahum VL - 7 PY - 2018 DA - 2018/06/22 SP - e32563 C1 - eLife 2018;7:e32563 DO - 10.7554/eLife.32563 UR - https://doi.org/10.7554/eLife.32563 AB - Translation initiation is the rate-limiting step of protein synthesis that is downregulated during the Integrated Stress Response (ISR). Previously, we demonstrated that most human mRNAs that are resistant to this inhibition possess translated upstream open reading frames (uORFs), and that 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 supports the derepression of downstream translation as a general mechanism of uORF-mediated stress resistance. It predicts that stress resistance can be achieved with long slowly decoded uORFs that do not favor translation reinitiation and that start with initiators of low leakiness. KW - uORF KW - TASEP KW - mRNA KW - integrated stress response KW - translation KW - eIF2 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -