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Molecular and Cellular Biology, December 2006, p. 9220-9231, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01453-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Autophagy Is Activated for Cell Survival after Endoplasmic Reticulum Stress{triangledown}

Maiko Ogata,1,2,{dagger} Shin-ichiro Hino,1,{dagger} Atsushi Saito,1,2 Keisuke Morikawa,2 Shinichi Kondo,1 Soshi Kanemoto,1,2 Tomohiko Murakami,1,2 Manabu Taniguchi,3 Ichiro Tanii,1 Kazuya Yoshinaga,1 Sadao Shiosaka,2 James A. Hammarback,4 Fumihiko Urano,5 and Kazunori Imaizumi1*

Division of Molecular and Cellular Biology, Department of Anatomy,Faculty of Medicine, University of Miyazaki, Kihara 5200, Kiyotake, Miyazaki 889-1692, Japan,1 Division of Structural Cellular Biology, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0101, Japan,2 Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan,3 Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157,4 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 016055

Received 7 August 2006/ Returned for modification 15 August 2006/ Accepted 22 September 2006

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.

* Corresponding author. Mailing address: Division of Molecular and Cellular Biology, Department of Anatomy, Faculty of Medicine, University of Miyazaki, Kihara 5200, Kiyotake, Miyazaki 889-1692, Japan. Phone: 81-985-85-1783. Fax: 81-985-85-9851. E-mail: imaizumi{at}med.miyazaki-u.ac.jp.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, December 2006, p. 9220-9231, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01453-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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