Abstract
Smac/Diablo and HtrA2/Omi promote apoptosis by binding to and antagonizing IAP proteins, including the ‘X chromosome-linked inhibitor of apoptosis’ (XIAP). Here we show that caspase-mediated proteolysis of a limited subset of cell death substrates exposes functional Smac/Diablo-like N-termini after cleavage, which are able to bind to and antagonize XIAP. We propose that this mechanism may establish a feedforward sensitization of the apoptotic pathway and contribute to the functional redundancy of IAP antagonism. In addition, this may be particularly relevant in Alzheimer's disease since the caspase-generated C31 peptide, an established cytotoxin, acquires Smac/Diablo-like properties after apoptotic processing.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- caspase:
-
cysteinyl aspartate-specific proteinase
- IAP:
-
inhibitor of apoptosis proteins
- XIAP:
-
X-linked IAP
- BIR:
-
baculovirus IAP repeat
- Smac:
-
second mitochondria-derived activator of caspase
- Diablo:
-
direct IAP-binding protein with low pI
- APP:
-
amyloid-β precursor protein
References
Deveraux QL, Takahashi R, Salvesen GS and Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388: 300–304
Du C, Fang M, Li Y, Li L and Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102: 33–42
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102: 43–53
Srinivasula SM, Datta P, Fan XP, Fernandes-Alnemri T, Huang Z and Alnemri ES (2000) Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. J. Biol. Chem. 275: 36152–36157
Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K and Takahashi R (2000) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol. Cell 8: 613–621
Hegde R, Srinisasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri R and Alnemri ES (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein–caspase interaction. J. Biol. Chem. 277: 432–438
Martins LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR, Savopoulos J, Gray CW, Creasy CL, Dingwall C and Downward J (2002) The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J. Biol. Chem. 277: 439–444
Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ and Vaux DL (2002) HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J. Biol. Chem. 277: 445–454
Nicholson DW (1999) Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 6: 1028–1042
Roy S and Nicholson DW (2000) Criteria for identifying authentic caspase substrates during apoptosis. Methods Enzymol. 322: 110–125
Fischer U, Jänicke RU and Schulze-Osthoff K (2003) Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ. 10: 76–100
Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS and Reed JC (1999) Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J. 18: 5242–5251
Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LHT, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S and Nicholson DW (1999) Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-β precursor protein and amyloidogenic Aβ peptide formation. Cell 97: 395–406
Lu DC, Rabizadeh S, Chandra S, Shayya RF, Ellerby LM, Ye X, Salvesen GS, Koo EH and Bredesen DE (2000) A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat. Med. 6: 397–404
Huang Y, Park YC, Rich RL, Segal D, Myszka DG and Wu H (2001) Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Cell 104: 781–790
Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC and Fesik SW (2000) Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 408: 1004–1008
Liu X, Kim CN, Yang J, Jemmerson R and Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Nature 86: 147–157
Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju AM, Smulson ME, Yamin T-T, Yu VL and Miller DK (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376: 37–43
Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, Lee RA, Robbins PD, Fernandes-Alnemri T, Shi Y and Alnemri ES (2001) A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 410: 112–116
Okada H, Suh W-K, Jin J, Woo M, Du C, Elia A, Duncan GS, Wakeham A, Itie A, Lowe SW, Wang X and Mak TW (2002) Generation and characterization of Smac/DIABLO-deficient mice. Mol. Cell Biol. 22: 3509–3517
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by G Melino
Rights and permissions
About this article
Cite this article
Hell, K., Saleh, M., Crescenzo, G. et al. Substrate cleavage by caspases generates protein fragments with Smac/Diablo-like activities. Cell Death Differ 10, 1234–1239 (2003). https://doi.org/10.1038/sj.cdd.4401298
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.cdd.4401298
Keywords
This article is cited by
-
More alive than dead: non-apoptotic roles for caspases in neuronal development, plasticity and disease
Cell Death & Differentiation (2017)
-
Apoptosis induction of U937 human leukemia cells by diallyl trisulfide induces through generation of reactive oxygen species
Journal of Biomedical Science (2012)
-
The mitochondrial serine protease HtrA2/Omi: an overview
Cell Death & Differentiation (2008)
-
Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin
International Journal of Hematology (2008)
-
Caspase substrates
Cell Death & Differentiation (2007)
