ER stress triggers apoptosis by activating BH3-only protein Bim

被引:1207
作者
Puthalakath, Hamsa
O'Reilly, Lorraine A.
Gunn, Priscilla
Lee, Lily
Kelly, Priscilla N.
Huntington, Nicholas D.
Hughes, Peter D.
Michalak, Ewa M.
McKimm-Breschkin, Jennifer
Motoyama, Noburo
Gotoh, Tomomi
Akira, Shizuo
Bouillet, Philippe
Strasser, Andreas [1 ]
机构
[1] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia
[2] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia
[3] CSIRO, Div Mol & Hlth Technol, Melbourne, Vic, Australia
[4] Natl Ctr Geriatr & Gerontol, Natl Inst Longev Sci, Dept Geriatr Med, Aichi, Japan
[5] Kumamoto Univ, Dept Mol Genet, Kumamoto 8608556, Japan
[6] Osaka Univ, Dept Host Def, Suita, Osaka 5650871, Japan
[7] Univ Melbourne, Dept Biochem, Bio21, Parkville, Vic 3052, Australia
[8] Inst Pasteur, Dept Immunol, Cytokine & Lymphoid Dev Unit, F-75724 Paris, France
关键词
D O I
10.1016/j.cell.2007.04.027
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 caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-onlymember of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBP alpha-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.
引用
收藏
页码:1337 / 1349
页数:13
相关论文
共 35 条
  • [1] Pin1 mediates neural-specific activation of the mitochondrial apoptotic machinery
    Becker, EBE
    Bonni, A
    [J]. NEURON, 2006, 49 (05) : 655 - 662
  • [2] Polycystic kidney disease prevented by transgenic RNA interference
    Bouillet, P
    Robati, M
    Bath, M
    Strasser, A
    [J]. CELL DEATH AND DIFFERENTIATION, 2005, 12 (07) : 831 - 833
  • [3] Proapoptotic Bcl-2 relative bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity
    Bouillet, P
    Metcalf, D
    Huang, DCS
    Tarlinton, DM
    Kay, TWH
    Köntgen, F
    Adams, JM
    Strasser, A
    [J]. SCIENCE, 1999, 286 (5445) : 1735 - 1738
  • [4] Gene structure, alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim
    Bouillet, P
    Zhang, LC
    Huang, DCS
    Webb, GC
    Bottema, CDK
    Shore, P
    Eyre, HJ
    Sutherland, GR
    Adams, JM
    [J]. MAMMALIAN GENOME, 2001, 12 (02) : 163 - 168
  • [5] BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes
    Bouillet, P
    Purton, JF
    Godfrey, DI
    Zhang, LC
    Coultas, L
    Puthalakath, H
    Pellegrini, M
    Cory, S
    Adams, JM
    Strasser, A
    [J]. NATURE, 2002, 415 (6874) : 922 - 926
  • [6] Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1
    Dijkers, PF
    Medema, RH
    Lammers, JWJ
    Koenderman, L
    Coffer, PJ
    [J]. CURRENT BIOLOGY, 2000, 10 (19) : 1201 - 1204
  • [7] Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreactive B cells
    Enders, A
    Bouillet, P
    Puthalakath, H
    Xu, YK
    Tarlinton, DM
    Strasser, A
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 198 (07) : 1119 - 1126
  • [8] SOLUBLE ATP-DEPENDENT PROTEOLYTIC SYSTEM RESPONSIBLE FOR DEGRADATION OF ABNORMAL PROTEINS IN RETICULOCYTES
    ETLINGER, JD
    GOLDBERG, AL
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1977, 74 (01) : 54 - 58
  • [9] Differential inhibition and posttranslational modification of protein phosphatase 1 and 2A in MCF7 cells treated with calyculin-A, okadaic acid, and tautomycine
    Favre, B
    Turowski, P
    Hemmings, BA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (21) : 13856 - 13863
  • [10] Activated T cell death in vivo mediated by proapoptotic Bcl-2 family member Bim
    Hildeman, DA
    Zhu, YN
    Mitchell, TC
    Bouillet, P
    Strasser, A
    Kappler, J
    Marrack, P
    [J]. IMMUNITY, 2002, 16 (06) : 759 - 767