Alternative translation mechanisms in health and disease

Abstract

Regulation of translation provides the cell with the plasticity needed to respond to rapid changes in the environment. Given that translation consumes more than 50% of cell's energy, it is not surprising that translation is tightly regulated. In many aberrant cellular processes, the translation machinery and translation output (ie proteome) are modified. This is often the case in various stress responses and disease states such as cancer and neurodegeneration. Global translation is reduced in response to rnost, if not ali, cellular stresses. Remarkably, this is often accompanied by a switch to selective translation of proteins that are required for cell survival under stress conditions. Most commonly, these use alternative modes of translation initiation involving the bypass of an upstream open reading frame (uORF) or the use of the Internal Ribosome Site Entry (IRES) mechanism. The Holcik laboratory investigates the mechanism(s) of IRES-dependent translation. The Castilho laboratory studies the stress-activated kinase, GCN2, a general translation inhibitor, and its negative regulator, IMPACT. The aim of this proposal is to investigate translational reprograming controlled by GCN2/IMPACT. This proposal is anchored on our mutual interest in understanding the mechanism of selective translation. The combined expertise of our groups will be instrumental in establishing and sustaining a productive collaboration that may unravel molecular events required for cells and organisms to cope with physiological perturbations. (AU)