TASEP modelling provides a parsimonious explanation for the ability of a single uORF to derepress translation during the integrated stress response
Dmitry E Andreev,
Maxim Arnold,
Stephen J Kiniry,
Gary Loughran,
Audrey M Michel,
Dmitrii Rachinskii,
Pavel V Baranov
Affiliations
Dmitry E Andreev
School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
Maxim Arnold
Department of Mathematical Sciences, The University of Texas at Dallas, Richardson, United States
Stephen J Kiniry
School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
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.
