RESUMEN
Cellular senescence is triggered by diverse stimuli and is characterized by long-term growth arrest and secretion of cytokines and chemokines (termed the SASP-senescence-associated secretory phenotype). Senescence can be organismally beneficial as it can prevent the propagation of damaged or mutated clones and stimulate their clearance by immune cells. However, it has recently become clear that senescence also contributes to the pathophysiology of aging through the accumulation of damaged cells within tissues. Here, we describe that inhibition of the reaction catalysed by LSG1, a GTPase involved in the biogenesis of the 60S ribosomal subunit, leads to a robust induction of cellular senescence. Perhaps surprisingly, this was not due to ribosome depletion or translational insufficiency, but rather through perturbation of endoplasmic reticulum homeostasis and a dramatic upregulation of the cholesterol biosynthesis pathway. The underlying transcriptomic signature is shared with several other forms of senescence, and the cholesterol biosynthesis genes contribute to the cell cycle arrest in oncogene-induced senescence. Furthermore, targeting of LSG1 resulted in amplification of the cholesterol/ER signature and restoration of a robust cellular senescence response in transformed cells, suggesting potential therapeutic uses of LSG1 inhibition.
Asunto(s)
Senescencia Celular/genética , Estrés del Retículo Endoplásmico/genética , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Subunidades Ribosómicas Grandes de Eucariotas/metabolismo , Puntos de Control del Ciclo Celular/genética , Colesterol/biosíntesis , Retículo Endoplásmico/metabolismo , Fibroblastos/metabolismo , Técnicas de Silenciamiento del Gen , Células HEK293 , Homeostasis/genética , Humanos , Biosíntesis de Proteínas/genética , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/metabolismo , Transcriptoma , Transfección , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Hundreds of putative enzymes from Mycobacterium tuberculosis as well as other mycobacteria remain categorized as "conserved hypothetical proteins" or "hypothetical proteins", offering little or no information on their functional role in pathogenic and non-pathogenic processes. In this study we have predicted the fold and 3-D structure of more than 99% of all proteins encoded in the genome of M. tuberculosis H37Rv. Fold-recognition, database search, 3-D modelling was performed using Protein Homology/analogy Recognition Engine V 2.0 (Phyre2). These results are used to tentatively assign potential function for unannotated enzymes and proteins. In summary, fold-recognition and structural homology might be used as a complementary tool in genome annotation efforts and furthermore, it can deliver primary sequence-independent information regarding structure, ligands and even substrate specificity for enzymes that display low primary sequence identity with potential homologues in other species.