Translocation of bim to the endoplasmic reticulum (ER) mediates ER stress signaling for activation of caspase-12 during ER stress-induced apoptosis

被引:155
作者
Morishima, N
Nakanishi, K
Tsuchiya, K
Shibata, T
Seiwa, E
机构
[1] RIKEN, Inst Phys & Chem Res, Bioarchitect Res Grp, Wako, Saitama 3510198, Japan
[2] RIKEN, Inst Phys & Chem Res, Cellular & Mol Biol Lab, Wako, Saitama 3510198, Japan
[3] Saitama Univ, Dept Mol Biol, Fac Sci & Engn, Saitama 3388570, Japan
关键词
D O I
10.1074/jbc.M408493200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:50375 / 50381
页数:7
相关论文
共 42 条
[31]   Cell death regulation by the Bcl-2 protein family in the mitochondria [J].
Tsujimoto, Y .
JOURNAL OF CELLULAR PHYSIOLOGY, 2003, 195 (02) :158-167
[32]  
Wang XD, 2001, GENE DEV, V15, P2922
[33]   Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death [J].
Wei, MC ;
Zong, WX ;
Cheng, EHY ;
Lindsten, T ;
Panoutsakopoulou, V ;
Ross, AJ ;
Roth, KA ;
MacCregor, GR ;
Thompson, CB ;
Korsmeyer, SJ .
SCIENCE, 2001, 292 (5517) :727-730
[34]   Movement of Bax from the cytosol to mitochondria during apoptosis [J].
Wolter, KG ;
Hsu, YT ;
Smith, CL ;
Nechushtan, A ;
Xi, XG ;
Youle, RJ .
JOURNAL OF CELL BIOLOGY, 1997, 139 (05) :1281-1292
[35]   Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis [J].
Zamzami, N ;
Marchetti, P ;
Castedo, M ;
Hirsch, T ;
Susin, SA ;
Masse, B ;
Kroemer, G .
FEBS LETTERS, 1996, 384 (01) :53-57
[36]   Signaling the unfolded protein response from the endoplasmic reticulum [J].
Zhang, KZ ;
Kaufman, RJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (25) :25935-25938
[37]   Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation [J].
Zheng, TS ;
Hunot, S ;
Kuida, K ;
Momoi, T ;
Srinivasan, A ;
Nicholson, DW ;
Lazebnik, Y ;
Flavell, RA .
NATURE MEDICINE, 2000, 6 (11) :1241-1247
[38]   Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types [J].
Zhu, WJ ;
Cowie, A ;
Wasfy, GW ;
Penn, LZ ;
Leber, B ;
Andrews, DW .
EMBO JOURNAL, 1996, 15 (16) :4130-4141
[39]   CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum [J].
Zinszner, H ;
Kuroda, M ;
Wang, XZ ;
Batchvarova, N ;
Lightfoot, RT ;
Remotti, H ;
Stevens, JL ;
Ron, D .
GENES & DEVELOPMENT, 1998, 12 (07) :982-995
[40]   BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak [J].
Zong, WX ;
Lindsten, T ;
Ross, AJ ;
MacGregor, GR ;
Thompson, CB .
GENES & DEVELOPMENT, 2001, 15 (12) :1481-1486