Autophagy is activated for cell survival after endoplasmic reticulum stress.
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.
Ogata
Maiko
M
Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, Kihara 5200, Kiyotake, Miyazaki 889-1692, Japan.
Hino
Shin-ichiro
S
Saito
Atsushi
A
Morikawa
Keisuke
K
Kondo
Shinichi
S
Kanemoto
Soshi
S
Murakami
Tomohiko
T
Taniguchi
Manabu
M
Tanii
Ichiro
I
Yoshinaga
Kazuya
K
Shiosaka
Sadao
S
Hammarback
James A
JA
Urano
Fumihiko
F
Imaizumi
Kazunori
K
D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D017510:Protein Folding; D015398:Signal Transduction; D013312:Stress, Physiological / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
D048031:JNK Mitogen-Activated Protein Kinases