A Bax/Bak-independent mitochondrial death pathway triggered by Drosophila Grim GH3 domain in mammalian cells

被引:26
作者
Clavería, C [1 ]
Martínez, C [1 ]
Torres, M [1 ]
机构
[1] Univ Autonoma Madrid, Dept Immunol & Oncol, Ctr Nacl Biotecnol, CSIC, E-28049 Madrid, Spain
关键词
D O I
10.1074/jbc.M309819200
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
Grim encodes a protein required for programmed cell death in Drosophila, whose proapoptotic activity is conserved in mammalian cells. Two proapoptotic domains are relevant for Grim killing function; the N-terminal region, which induces apoptosis by disrupting inhibitor of apoptosis protein (IAP) blockage of caspase activity, and the internal GH3 domain, which triggers a mitochondrial pathway. We explored the role of these two domains in heterologous killing of mammalian cells by Grim. The GH3 domain is essential for Grim proapoptotic activity in mouse cells, whereas the N-terminal domain is dispensable. The GH3 domain is required and sufficient for Grim targeting to mitochondria and for cytochrome c release in a caspase-and N-terminal-independent, IAP-insensitive manner. These Grim GH3 activities do not require Bax or Bak function, revealing GH3 activity as the first proapoptotic stimulus able to trigger the mitochondrial death pathway in mammalian cells in the absence of multidomain proapoptotic Bcl-2 proteins.
引用
收藏
页码:1368 / 1375
页数:8
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