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Previous Article | Next Article
The Journal of Neuroscience, March 15, 2002, 22(6):2035-2043
The Neuronal Apoptosis Inhibitory Protein Is a Direct Inhibitor of Caspases 3 and 7
Johannes K. X. Maier1, 2, Zahia Lahoua1, Nathalie H. Gendron1, Raouf Fetni1, Anne Johnston1, Jamshid Davoodi1, Dita Rasper4, Sophie Roy4, Ruth S. Slack3, Donald W. Nicholson4, and Alex E. MacKenzie1, 2, 5 1 Solange Gauthier Karsh Laboratory, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada K1H 8L1, 2 Department of Biochemistry, Microbiology, and Immunology, and 3 Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5, 4 Merck Frosst Canada Inc., Kirkland, Quebec, Canada H9H 3L1, and 5 Aegera Therapeutics Inc., Ottawa, Ontario, Canada K1H 8M5
The neuronal apoptosis inhibitory protein (NAIP) was identified as a candidate gene for the inherited neurodegenerative disorder spinal muscular atrophy. NAIP is the founding member of a human protein family that is characterized by highly conserved N-terminal motifs called baculovirus inhibitor of apoptosis repeats (BIR). Five members of the human family of inhibitor of apoptosis proteins including NAIP have been shown to be antiapoptotic in various systems. To date, a mechanism for the antiapoptotic effect of NAIP has not been elucidated. To investigate NAIP function, we found cytoprotection of NAIP-expressing primary cortical neurons treated to undergo caspase-3-dependent apoptosis. The additional treatment of these neurons with the pancaspase inhibitor boc-aspartyl(OMe)-fluoromethylketone did not result in increased survival. Similar cytoprotective effects were obtained using HeLa cells transiently transfected with a NAIP N-terminal construct and treated to undergo a caspase-3-dependent cell death. To examine whether NAIP inhibits caspases directly, recombinant N-terminal NAIP protein containing BIR domains was overexpressed, purified, and tested for caspase inhibition potential. Our results demonstrate that inhibition of caspases is selective and restricted to the effector group of caspases, with Ki values as low as ~14 nM for caspase-3 and ~45 nM for caspase-7. Additional investigations with NAIP fragments containing either one or two NAIP BIRs revealed that the second BIR and to a lesser extent the third BIR alone are sufficient to mediate full caspase inhibition.
Key words: BIR domains; NAIP; caspase inhibition; neuronal apoptosis; inhibitor of apoptosis protein family; cytoprotection
Copyright © 2002 Society for Neuroscience 0270-6474/02/2262035-09$05.00/0
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