The antiapoptotic activity of insect IAPs requires activation by an evolutionarily conserved mechanism.
Apoptosis represents a fundamental biological process that relies on the activation of caspases. Inhibitor of apoptosis (IAP) proteins represent a group of negative regulators of both caspases and cell death. The current model dictates that IAPs suppress apoptosis by blocking the catalytic pocket of effector caspases thereby preventing substrate entry. Here, we provide evolutionary evidence for the functional interplay between insect IAPs and the N-end rule-associated ubiquitylation machinery in neutralising effector caspases and cell death. We find that IAPs require 'priming' in order to function as antiapoptotic molecules. Consistently, we demonstrate that the antiapoptotic activity of diverse insect IAPs is activated by effector caspases, providing the cell with a sensitive strategy to monitor and neutralise active caspases. Almost 300 million years of evolutionary selection pressure has preserved a caspase cleavage site in insect IAPs that, following processing by a caspase, exposes a binding motif for the N-end-rule-associated degradation machinery. Recruitment of this ubiquitylation machinery into the 'cleaved-IAP:caspase' complex provides a mechanism to negatively regulate effector caspases and block apoptosis. Furthermore, comparisons between cellular and several viral IAPs suggest differences in their modes of action, as OpIAP3, CpGV-IAP3 and HcNPV-IAP3 fail to associate with several effector caspases. Evolutionary conservation of the N-end-rule degradation pathway in IAP-mediated regulation of apoptosis further corroborates the physiological relevance of this ubiquitylation-associated process.
Tenev
T
T
The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
Ditzel
M
M
Zachariou
A
A
Meier
P
P
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004330:Drosophila / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D051381:Rats; D017386:Sequence Homology, Amino Acid
D051034:Inhibitor of Apoptosis Proteins; D020169:Caspases