ATF6α regulates morphological changes associated with senescence in human fibroblasts

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.

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…Moreover, as shown in the hepatocellular carcinoma model, ATF6 may be involved in the regulation of cell proliferation (57) or in the sensitivity to chemotherapy in leukemia cells (58). Data also suggest ATF6 contribution to cancer progression by shaping tumor microenvironment (59) as well as in the induction of the senescent phenotype (60). In summary, accumulating evidence suggests that activation of the UPR may affect multiple aspects related to cancer progression beyond its classical role in tumor adaptation against hypoxia.…”

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…However, several experiments in vitro have revealed that the ER stress-induced UPR is rather the inducer of cellular senescence and not only an outcome. Druelle et al [13] reported that ATF6α signaling controls many morphological aspects of the replicative senescence of human fibroblasts. The silencing of ATF6α signaling could partly reverse the ER expansion and SASP of senescent cells.…”

“…ER stress is closely associated with both aging and AD pathology (see below). For instance, ER stress is connected to the generation of cellular senescence [12][13][14]. The number of senescent cells progressively increases with aging.…”

The p38‐activated ER stress‐ATF6α axis mediates cellular senescence

“…Also, ATF6a-dependent transcription increased after NBR1 abrogation, as demonstrated by a reporter assay. Recently, it has been reported that ATF6a regulates the morphologic changes associated with cellular senescence (39).…”