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  • Original Paper
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The C. elegans orthologue ceBNIP3 interacts with CED-9 and CED-3 but kills through a BH3- and caspase-independent mechanism

Oncogene volume 19, pages 5453–5463 (2000)Cite this article

Abstract

We have studied ceBNIP3, the orthologue of BNIP3 in C. elegans. Sequence analysis reveals that the different domains of BNIP3 have been conserved throughout evolution. ceBNIP3 contains a C-terminal transmembrane (TM) domain, a conserved domain (CD) of 19 amino acids, a BCL-2 homology-3 (BH3)-like domain and a PEST sequence. ceBNIP3 is expressed primarily as a 25 kDa monomer and a 50 kDa homodimer. After transfection, ceBNIP3 protein is rapidly degraded through a ubiquitin-dependent pathway by the proteasome. Like BNIP3, the TM domain of ceBNIP3 mediates the localization of the protein to mitochondria and is also necessary for homodimerization and cell death in mammalian cells. Neither the putative BH3 domain nor conserved domain is necessary for killing. ceBNIP3 protein interacts with CED-9 and BCL-XL, but unlike other pro-apoptotic BCL-2 family members, the BH3-like domain does not participate in dimerization. The ceBNIP3 TM domain mediates interaction with both CED-9 and BCL-XL. ceBNIP3 interacts with CED-3 but co-expression of CED-3 and ceBNIP3 does not significantly enhance induction of cell death in the presence or absence of CED-4. ceBNIP3 kills mammalian cells by a caspase-independent mechanism. In conclusion, we find that although ceBNIP3 interacts with CED-9 and CED-3 it kills by a BH3- and caspase-independent mechanism.

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Acknowledgements

We thank Dr Dwight Nance for help in the confocal studies, Dr Radhey Gupta for anti-HSP60 antibody, Dr Gabriel Nunez for providing the CED-9 and CED-3 cDNAs, Dr Gordon Shore for the Bcl-XL plasmid, Dr Peter Okkema for the C. elegans cDNA library and Dr Harvey Ozer for the TS20 cell line. Also, we thank Laurie Lange for her technical help with the FISH microscope. This work was supported by the NCIC and Canadian Health Research Institute.

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  1. Gao Chen

    Present address: The Institute for Biological Sciences, Ottawa, Ontario, K1A 0R6, Canada

Authors and Affiliations

  1. Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, R3E 0V9, Canada

    Jeannick Cizeau, Reena Ray, Gao Chen & Arnold H Greenberg

  2. Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, R3E 0W3, Manitoba, Canada

    Reena Ray & R Daniel Gietz

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  1. Jeannick Cizeau
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Cizeau, J., Ray, R., Chen, G. et al. The C. elegans orthologue ceBNIP3 interacts with CED-9 and CED-3 but kills through a BH3- and caspase-independent mechanism. Oncogene 19, 5453–5463 (2000). https://doi.org/10.1038/sj.onc.1203929

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