RESUMEN
Phosphorylation of the translation initiation factor eIF2α is a rapid and vital response to many forms of stress, including protein-misfolding stress in the endoplasmic reticulum (ER stress). It is believed to cause a general reduction in protein synthesis while enabling translation of few transcripts. Such a reduction of protein synthesis comes with the threat of depleting essential proteins, a risk thought to be mitigated by its transient nature. Here, we find that translation attenuation is not uniform, with cytosolic and mitochondrial ribosomal subunits being prominently downregulated. Translation attenuation of these targets persists after translation recovery. Surprisingly, this occurs without a measurable decrease in ribosomal proteins. Explaining this conundrum, translation attenuation preferentially targets long-lived proteins, a finding not only demonstrated by ribosomal proteins but also observed at a global level. This shows that protein stability buffers the cost of translational attenuation, establishing an evolutionary principle of cellular robustness.
Asunto(s)
Factor 2 Eucariótico de Iniciación/metabolismo , Biosíntesis de Proteínas , Regiones no Traducidas 5'/genética , Animales , Regulación hacia Abajo/genética , Estrés del Retículo Endoplásmico/genética , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Modelos Biológicos , Células 3T3 NIH , Fosforilación , Polirribosomas/metabolismo , Estabilidad Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Ribosómicas/metabolismo , Transcripción Genética , Respuesta de Proteína Desplegada/genéticaRESUMEN
Structural mutants of p53 induce global p53 protein destabilization and misfolding, followed by p53 protein aggregation. First evidence indicates that p53 can be part of protein condensates and that p53 aggregation potentially transitions through a condensate-like state. We show condensate-like states of fluorescently labeled structural mutant p53 in the nucleus of living cancer cells. We furthermore identified small molecule compounds that interact with the p53 protein and lead to dissolution of p53 structural mutant condensates. The same compounds lead to condensation of a fluorescently tagged p53 DNA-binding mutant, indicating that the identified compounds differentially alter p53 condensation behavior depending on the type of p53 mutation. In contrast to p53 aggregation inhibitors, these compounds are active on p53 condensates and do not lead to mutant p53 reactivation. Taken together our study provides evidence for structural mutant p53 condensation in living cells and tools to modulate this process.