Intracellular Nucleotides Act as Critical Prosurvival Factors by Binding to Cytochrome C and Inhibiting Apoptosome

Cytochrome c (CC)-initiated Apaf-1 apoptosome formation represents a key initiating event in apoptosis. This process can be reconstituted in vitro with the addition of CC and ATP or dATP to cell lysates. How physiological levels of nucleotides, normally at high mM concentrations, affect apoptosome a...

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Bibliographic Details
Published in:Cell 2006-06, Vol.125 (7), p.1333-1346
Main Authors: Chandra, Dhyan, Bratton, Shawn B., Person, Maria D., Tian, Yanan, Martin, Angel G., Ayres, Mary, Fearnhead, Howard O., Gandhi, Varsha, Tang, Dean G.
Format: Article
Language:English
Subjects:
Apoptosis - physiology
Apoptotic Protease-Activating Factor 1
Binding Sites
Caspase 9
Caspases - metabolism
Cell Line
Cell Survival - physiology
Cell-Free System
Cytochromes c - chemistry
Cytochromes c - metabolism
Enzyme Activation
Humans
In Vitro Techniques
Intracellular Signaling Peptides and Proteins - chemistry
Intracellular Signaling Peptides and Proteins - metabolism
Lysine - chemistry
Models, Molecular
Multiprotein Complexes
Nucleotides - metabolism
Protein Conformation
Protein Structure, Quaternary
Proteins - chemistry
Proteins - metabolism
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Summary:Cytochrome c (CC)-initiated Apaf-1 apoptosome formation represents a key initiating event in apoptosis. This process can be reconstituted in vitro with the addition of CC and ATP or dATP to cell lysates. How physiological levels of nucleotides, normally at high mM concentrations, affect apoptosome activation remains unclear. Here we show that physiological levels of nucleotides inhibit the CC-initiated apoptosome formation and caspase-9 activation by directly binding to CC on several key lysine residues and thus preventing CC interaction with Apaf-1. We show that in various apoptotic systems caspase activation is preceded or accompanied by decreases in overall intracellular NTP pools. Microinjection of nucleotides inhibits whereas experimentally reducing NTP pools enhances both CC and apoptotic stimuli-induced cell death. Our results thus suggest that the intracellular nucleotides represent critical prosurvival factors by functioning as natural inhibitors of apoptosome formation and a barrier that cells must overcome the nucleotide barrier to undergo apoptosis cell death.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2006.05.026