RESUMEN
Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.
Asunto(s)
Senescencia Celular , Factor 5A Eucariótico de Iniciación de Traducción , Mitocondrias , Factores de Iniciación de Péptidos , Biosíntesis de Proteínas , Proteínas de Unión al ARN , Proteína p53 Supresora de Tumor , Factores de Iniciación de Péptidos/metabolismo , Factores de Iniciación de Péptidos/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Humanos , Mitocondrias/metabolismo , Animales , Ratones , Vigilancia Inmunológica , Poliaminas/metabolismo , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Lisina/metabolismo , Lisina/análogos & derivadosRESUMEN
Pediatric myelodysplastic syndrome (PMDS) is a very rare and still poorly characterized disorder. In this work, we identified novel potential targets of PMDS by determining genes with aberrant expression, which can be correlated with PMDS pathogenesis. We identified 291 differentially expressed genes (DEGs) in PMDS patients, comprising genes involved in the regulation of apoptosis and the cell cycle, ribosome biogenesis, inflammation and adaptive immunity. Ten selected DEGs were then validated, confirming the sequencing data. These DEGs will potentially represent new molecular biomarkers and therapeutic targets for PMDS.