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Substrate cleavage by caspases generates protein fragments with Smac/Diablo-like activities
K Hell1, M Saleh, G D Crescenzo
1Merck Research Laboratories, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8.
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.
Insights
New findings reveal that cleaved cell death substrates can mimic Smac/Diablo (SMAC/DIABLO) to inhibit IAP proteins like XIAP, enhancing apoptosis. This mechanism may be relevant in Alzheimer's disease.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Inhibitor of Apoptosis Proteins (IAPs) regulate programmed cell death.
- Smac/Diablo (SMAC/DIABLO) and HtrA2/Omi antagonize IAPs, promoting apoptosis.
- X-linked inhibitor of apoptosis (XIAP) is a key IAP target.
Purpose of the Study:
- To investigate novel mechanisms of IAP antagonism.
- To explore the role of caspase-mediated cleavage in apoptosis regulation.
- To examine the relevance of these findings in Alzheimer's disease.
Main Methods:
- Analysis of caspase-mediated proteolysis of cell death substrates.
- Biochemical assays to assess binding of cleaved substrates to XIAP.
- Investigation of the functional consequences of substrate cleavage on apoptosis.
Main Results:
- Caspase cleavage of specific substrates exposes N-termini with Smac/Diablo-like activity.
- These cleaved substrates effectively bind and antagonize XIAP.
- The caspase-generated C31 peptide from Alzheimer's disease exhibits Smac/Diablo-like properties post-cleavage.
Conclusions:
- A novel feedforward mechanism sensitizes the apoptotic pathway.
- This process contributes to the functional redundancy of IAP antagonism.
- The findings suggest a potential role in Alzheimer's disease pathogenesis.