Abstract
Protein expression evolves under greater evolutionary constraint than mRNA levels, and translation efficiency represents a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate key biochemical pathways. For our first study: we uncover a network of RNA-binding proteins (RBPs) that enhance the translation efficiency of glycolytic proteins in cells responding to oxygen deprivation. A system-wide proteomic survey of translational engagement identifies a family of oxygen-regulated RBPs that functions as a switch of glycolytic intensity. Tandem mass tag-pulse SILAC and RNA sequencing reveals that each RBP controls a unique but overlapping portfolio of hypoxic responsive proteins. These RBPs collaborate with the hypoxic protein synthesis apparatus, operating as a translation efficiency checkpoint that integrates upstream mRNA signals to activate anaerobic metabolism and confer hypoxia tolerance. RBP-controlled anaerobic metabolism induces a concurrent acidification of the extracellular milieu. For our second study we identified the ancient eIF5A as a pH-regulated translation factor that responds to hypoxia-induced acidosis. Proteomic analysis identified several pH-dependent proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1. Sirt1 operates as a pH-sensor that deacetylates nuclear eIF5A during anaerobiosis, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement. Tsc2 induction inhibits mTORC1 to suppress cellular metabolism, induce cellular dormancy and prevent acidosis-induced DNA damage. We suggest cells are equipped with translatome remodelers that control anaerobiosis.