RESUMEN

Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochemical adaptations. Here, we identify a translational pathway that represses metabolism to safeguard genome integrity. A system-wide MATRIX survey identified the ancient eIF5A as a pH-regulated translation factor that responds to fermentation-induced acidosis. TMT-pulse-SILAC 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 and prevent acidosis-induced DNA damage. Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation, but at the expense of incurring substantial DNA damage. We suggest that eIF5A operates as a translatome remodeler that suppresses metabolism to shield the genome.

Asunto(s)

Daño del ADN , Factores de Iniciación de Péptidos/metabolismo , Biosíntesis de Proteínas , Proteínas de Unión al ARN/metabolismo , Acidosis/metabolismo , Acidosis/patología , Transporte Activo de Núcleo Celular , Adenosina Trifosfato/metabolismo , Hipoxia de la Célula , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Factores de Iniciación de Péptidos/genética , Proteómica , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/metabolismo , Transcripción Genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/metabolismo , Factor 5A Eucariótico de Iniciación de Traducción