Abstract
In Drosophila, the genetic locus 75CI1,2 is essential for all developmental cell death. Within this region are the genes for three pro-death proteins, Grim, Reaper and HID. These proteins are transcriptionally regulated and their expression tightly associated with cell death in the developing fly embryo. When ectopically expressed in the retina, Grim, Reaper and HID cause apoptosis and eye ablation. They have a short region of similarity at their N-termini through which they can interact with inhibitor of apoptosis (IAP) proteins, and it is by antagonising IAP inhibition of caspases that Grim, Reaper and HID promote cell death. The observation that Grim, Reaper and HID can interact with mammalian IAPs and induce apoptosis in mammalian cells suggested that mammalian IAP antagonists might also exist. Diablo/Smac, identified six years after the first description of a Drosophila IAP antagonist, is the only mammalian protein identified to date that is clearly functionally related to the Drosophila proteins. Since its discovery, there have been numerous studies investigating how Diablo/Smac interacts with IAPs and promotes cell death. Here we review what is currently known about Diablo/Smac and speculate on other mammalian IAP antagonists.
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References
Du CY, Fang M, Li YC, Li L, Wang XD Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102: 33–42.
Verhagen AM, Ekert PG, Pakusch M, et al Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000; 102: 43–53.
Ekert PG, Silke J, Hawkins CJ, Verhagen AM, Vaux DL DIABLO promotes apoptosis by removing MIHA/XIAP from processed caspase 9. Journal of Cell Biology 2001; 152: 483–490.
Verhagen AM, Coulson EJ, Vaux DL Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs. Genome Biol 2001; 2: 3009.1–3009.10.
Chai JJ, Du CY, Wu JW, Kyin S, Wang XD, Shi YG Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 2000; 406: 855–862.
Srinivasula SM, Datta P, Fan XJ, Fernandes-Alnemri T, Huang ZW, Alnemri ES Molecular determinants of the caspasepromoting activity of Smac/DIABLO and its role in the death receptor pathway. Journal of Biological Chemistry 2000; 275: 36152–36157.
White K, Grether ME, Abrams JM, Young L, Farrell K, Steller H Genetic control of programmed cell death in Drosophila [see comments]. Science 1994; 264: 677–683.
Grether ME, Abrams JM, Agapite J, White K, Steller H The head involution defective gene of drosophila melanogaster functions in programmed cell death. Genes &Development 1995; 9: 1694–1708.
Chen P, Nordstrom W, Gish B, Abrams JM Grim, a novel cell death gene in drosophila. Genes & Development 1996; 10: 1773–1782.
White K, Tahaoglu E, Steller H Cell killing by the drosophila gene reaper. Science 1996; 271: 805–807.
Vucic D, Kaiser WJ, Harvey AJ, Miller LK Inhibition of reaper-induced apoptosis by interaction with inhibitor of apoptosis proteins (iaps). Proceedings of the National Academy of Sciences of the United States of America 1997; 94: 10183–10188.
Vucic D, Kaiser WJ, Miller LK Inhibitor of apoptosis proteins physically interact with and block apoptosis induced by drosophila proteins hid and grim. Molecular & Cellular Biology 1998; 18: 3300–3309.
Wang SL, Hawkins CJ, Yoo SJ, Muller HAJ, Hay BA The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 1999; 98: 453–463.
Wu G, Chai JJ, Suber TL, et al Structural basis of IAP recognition by Smac/DIABLO. Nature 2000; 408: 1008–1012.
Liu ZH, Sun CH, Olejniczak ET, et al Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 2000; 408: 1004–1008.
Silke J, Verhagen AM, Ekert PG, Vaux DL Sequence as well as functional similarity for DIABLO/Smac and Grim, Reaper and Hid? Cell Death & Differentiation 2000; 7: 1275.
Wu J, Cocina AE, Chai J, Hay BA, Shi Y Structural analysis of a functional diap1 fragment bound to grim and hid peptides. Mol Cell 2001; 8: 95–104.
Srinivasula SM, Hegde R, Saleh A, et al A conserved XIAPinteraction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 2001; 410: 112–116.
Riedl SJ, Renatus M, Schwarzenbacher R, et al Structural basis for the inhibition of caspase-3 by XIAP. Cell 2001; 104: 791–800.
Huang YH, Park YC, Rich RL, Segal D, Myszka DG, Wu H Structural basis of caspase inhibition by XIAP: Differential roles of the linker versus the BIR domain. Cell 2001; 104: 781–790.
Chai JJ, Shiozaki E, Srinivasula SM, et al Structural basis of caspase-7 inhibition by XIAP. Cell 2001; 104: 769–780.
Silke J, Ekert PG, Day CL, et al Direct inhibition of caspase 3 is dispensable for the anti-apoptotic activity of XIAP. Embo J 2001; 20: 3114–3123.
Roberts DL, Merrison W, MacFarlane M, Cohen GM The inhibitor of apoptosis protein-binding domain of Smac is not essential for its proapoptotic activity. Journal of Cell Biology 2001; 153: 221–227.
Thress K, Evans EK, Kornbluth S Reaper-induced dissociation of a Scythe-sequestered cytochrome c-releasing activity. EMBO Journal 1999; 18: 5486–5493.
Liston P, Fong WG, Kelly NL, et al Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol 2001; 3: 128–133.