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J. Biol. Chem., Vol. 279, Issue 48, 50375-50381, November 26, 2004

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Translocation of Bim to the Endoplasmic Reticulum (ER) Mediates ER Stress Signaling for Activation of Caspase-12 during ER Stress-induced Apoptosis^*

Nobuhiro Morishima¶, Keiko Nakanishi||, Kyoko Tsuchiya, Takehiko Shibata, and Emiko Seiwa**

From the Bioarchitect Research Group and Cellular and Molecular Biology Laboratory, RIKEN (The Institute of Physical and Chemical Research), 2-1 Hirosawa, Wako, Saitama 351-0198, and the ^**Department of Molecular Biology, Faculty of Science and Engineering, Saitama University, 255 Shimo-Ohkubo, Saitama, Saitama 338-8570, Japan

Endoplasmic reticulum (ER) stress activates caspase-12 in murine cells, triggering the ER stress-specific cascade for implementation of apoptosis. In C2C12 murine myoblast cells, activation of the cascade occurs without release of cytochrome c from mitochondria, suggesting that the cascade is independent of mitochondrial damage. Stable overexpression of Bcl-xL in C2C12 cells suppressed activation of caspase-12 and apoptosis. In ER-stressed cells, but not in normal cells, Bcl-xL was co-immunoprecipitated with Bim, a pro-apoptotic member of the Bcl-2 family, suggesting that Bcl-xL sequesters Bim, thereby inhibiting the apoptotic signaling. Fractionation of C2C12 cells revealed that ER stress led to translocation of Bim from a dynein-rich compartment to the ER, while stable overexpression of Bcl-xL suppressed accumulation of Bim on the ER. Although the toxic effect of Bim had been previously observed only at the mitochondrial outer membrane, overexpression of a Bim derivative, Bim(ER), targeted at the surface of the ER led to apoptosis. A C2C12 transfectant overexpressing the caspase-12 suppressor protein was resistant to Bim(ER), suggesting that the toxic effect of Bim on the ER is dependent on activation of caspase-12. Knockdown of Bim by RNA interference provided cells resistant to ER stress. These results suggest that translocation of Bim to the ER in response to ER stress is an important step toward activation of caspase-12 and initiation of the ER stress-specific caspase cascade.

Received for publication, July 27, 2004 , and in revised form, September 13, 2004.

^* This work was supported in part by a grant from the Bioarchitect Research Project and by a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science (to N. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Junior Research Fellow of RIKEN.

Present address: Moritex Corp., Jingumae, Shibuya, Tokyo 150-0001, Japan.

^¶ To whom correspondence should be addressed. Tel.: 81-48-467-9538; Fax: 81-48-462-4671; E-mail: morishim{at}postman.riken.jp.

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