Abstract
Cellular senescence is known as an anti-tumor barrier and is characterized by a number of determinants including cell cycle arrest, senescence associated β-galactosidase activity and secretion of pro-inflammatory mediators. Senescent cells are also subjected to enlargement, cytoskeleton-mediated shape changes and organelle alterations. However, the underlying molecular mechanisms responsible for these last changes remain still uncharacterized. Herein, we have identified the Unfolded Protein Response (UPR) as a player controlling some morphological aspects of the senescent phenotype. We show that senescent fibroblasts exhibit ER expansion and mild UPR activation, but conserve an ER stress adaptive capacity similar to that of exponentially growing cells. By genetically invalidating the three UPR sensors in senescent fibroblasts, we demonstrated that ATF6α signaling dictates senescence-associated cell shape modifications. We also show that ER expansion and increased secretion of the pro-inflammatory mediator IL6 were partly reversed by silencing ATF6α in senescent cells. Moreover, ATF6α drives the increase of senescence associated-β-galactosidase activity. Collectively, these findings unveil a novel and central role for ATF6α in the establishment of morphological features of senescence in normal human primary fibroblasts.
Highlights
After a limited number of divisions, normal cells enter a cell cycle arrest state called senescence, while remaining viable and metabolically active [1]
We show that senescent cells elicit an Endoplasmic Reticulum (ER) expansion that leads to a progressive activation of the Unfolded Protein Response (UPR)
We demonstrate the key role of Activating Transcription Factor 6α (ATF6α) in this ER expansion which occurs in link with the establishment of the major senescence-associated morphological changes including the loss of the parallel organization of the cells, the loss of the fusiform shape
Summary
After a limited number of divisions, normal cells enter a cell cycle arrest state called senescence, while remaining viable and metabolically active [1]. Various mechanisms can induce senescence, including telomere shortening, DNA damage, oxidative stress or oncogene activation [4, 5]. The cell-cycle inhibitor p16INK4/Rb is robustly activated, in part in response to the oxidative stress which increases at senescence [7, 8]. Senescent cells exhibit profound morphological changes including increase in cell size, in spreading on the substratum and change in cell shape. IRE1α induces the unconventional splicing of XBP1 mRNA, allowing the translation of an active transcription factor, whose main targets are the genes involved in quality control of proteins in the ER. Our results suggest that the ATF6α branch of the UPR may represent a potential therapeutic target against senescence-associated cellular dysfunctions in the context of aging
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