Autophagy Is Activated for Cell Survival after Endoplasmic ReticulumStress

Abstract

Eukaryotic cells deal with accumulation of unfolded proteins in the endoplasmic reticulum (ER) by the unfolded protein response, involving the induction of molecular chaperones, translational attenuation, and ER-associated degradation, to prevent cell death. Here, we found that the autophagy system is activated as a novel signaling pathway in response to ER stress. Treatment of SK-N-SH neuroblastoma cells with ER stressors markedly induced the formation of autophagosomes, which were recognized at the ultrastructural level. The formation of green fluorescent protein (GFP)-LC3-labeled structures (GFP-LC3 "dots"), representing autophagosomes, was extensively induced in cells exposed to ER stress with conversion from LC3-I to LC3-II. In IRE1-deficient cells or cells treated with c-Jun N-terminal kinase (JNK) inhibitor, the autophagy induced by ER stress was inhibited, indicating that the IRE1-JNK pathway is required for autophagy activation after ER stress. In contrast, PERK-deficient cells and ATF6 knockdown cells showed that autophagy was induced after ER stress in a manner similar to the wild-type cells. Disturbance of autophagy rendered cells vulnerable to ER stress, suggesting that autophagy plays important roles in cell survival after ER stress.

Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress

“…When treated with ER stress, atg5 À/À cells died faster than atg5 þ / þ cells (Supplementary Figure S5D), consistent with recent reports that autophagy acts as a survival mechanism to suppress apoptosis in response to ER stress. 16,17 As anticipated, Bcl-xL protected both atg5 þ / þ and atg5 À/À cells from acute apoptosis. In response to prolonged ER stress the Bcl-xLoverexpressing cells progressively died.…”

“…[16][17][18][19] In contrast, in apoptosis-deficient cells prolonged autophagy provokes cell death, and its absence imparts protection. This may be because in these cells where excessive ER stress fails to induce apoptosis, the stressing situation keeps accumulating to a point where autophagy is massively induced subsequently leading to cell damage and necrosis.…”

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

“…Studies reported that ER stress led to autophagy [30][31][32] and that RINT1 was associated with autophagy. 21 Therefore, we decided to monitor autophagy in Rint1-deficient cortices.…”

Role of the pro-survival molecule Bfl-1 in melanoma

“…These vesicles, termed autophagosomes, then fuse to lysosomes, forming autolysosomes, which break down the contents of the vesicle (Figure 1.4). Autophagy can be induced under a range of situations and stimuli, including growth factor withdrawal 114 , inhibition of degradation by the ubiquitin-proteasome system 115 , increases in cytosolic calcium 116 and endoplasmic reticulum stress 117 . Morphologically, autophagy can be identified by electron microscopy where cytoplasmic vacuolation without chromatin condensation is observed.…”