Translational Control by Molecular Chaperones: The Unexplored Mechanisms Coordinating Protein Synthesis and Proteostasis in Health and Genetic Reprogramming

CHAPEROME aims to establish a new concept in which molecular chaperones regulate central aspects of mRNA translation in human cells under physiological conditions, in response to proteotoxic stress, and during cellular differentiation. Recent findings indicate that the folding of translation factors relies on specific chaperone proteins to achieve their functional states. We hypothesize that chaperones play a pivotal role in aligning translation rates, efficiency, and mRNA selection with the cell’s proteostasis needs, thus acting as folding sensors that link protein synthesis to cellular demands. Testing this hypothesis requires collaboration among experts in translation, nascent chain folding, and chaperone mechanisms. Establishing this new concept for regulation of translation involves a comprehensive identification of chaperone dependencies of translation factors, which will reveal how chaperone networks control their functionality and impact translation rate and efficiency (Aim 1). We will elucidate the mechanisms by which chaperones and cofactors regulate elongation rates through interactions with nascent protein chains and translation factors, showing new connections between translation and protein folding under physiological conditions. Inducing proteotoxic stress to trigger chaperone overload will reveal the importance of chaperone regulation of translation (Aim 2). Finally, we will examine the new concept in the context of cellular differentiation, to understand how translation and chaperone networks adapt to drastic changes in cell type-specific proteome needs. This will provide novel insight into the plasticity of the translation-chaperone regulatory systems (Aim 3). This interdisciplinary and synergistic effort will reveal new key principles of translation regulation, proteostasis, and cell differentiation, potentially identifying novel targets for diseases associated with translation dysregulation.