부산대학교 도서관

The accumulation of senescent cells is recognised as a driver of tissue and organismal ageing. One of the gold‐standard hallmarks of a senescent cell is an increase in lysosomal content, as measured by senescence‐associated β‐galactosidase (Senβ‐Gal) activity. The lysosome plays a central role in integrating mitogenic and stress cues to control cell metabolism, which is known to be dysregulated in senescence. Despite this, little is known about the cause and consequence of lysosomal biogenesis in senescence. We find here that lysosomes in senescent cells are dysfunctional; they have higher pH, increased evidence of membrane damage and reduced proteolytic capacity. The significant increase in lysosomal content is however sufficient to maintain degradative capacity of the cell to a level comparable to proliferating control cells. We demonstrate that increased nuclear TFEB/TFE3 supports lysosome biogenesis, is a hallmark of multiple forms of senescence and is required for senescent cell survival. TFEB/TFE3 are hypo‐phosphorylated and show constitutive nuclear localisation in senescence. Evidence suggests that several pathways may contribute to TFEB/TFE3 dysregulation in senescence. Synopsis: Increased lysosomal content is a hallmark of cellular senescence. Here we show that senescent lysosomes are dysfunctional, but the activation of the transcription factor TFEB/TFE3 drives lysosome biogenesis and cell survival. Senescence is associated with an increase in dysfunctional lysosomes.Increased lysosomal content maintains a degradative capacity in senescent cells that is comparable to proliferating cells, suggesting the existence of mechanisms that define a catabolic "set‐point".TFEB/TFE3 are dephosphorylated and constitutively localised to the nucleus in senescence.Multiple mechanisms are likely to contribute to TFEB/TFE3 activation, including p16/INK4a‐CDK4 and RagC‐mTORC1.Targeting lysosomes, either by TFEB/TFE3 knock‐down or pharmacologically, causes senescent cell death. [ABSTRACT FROM AUTHOR]