Intrinsic apoptosis is evolutionary divergent among metazoans

Abstract

SummaryApoptosis is characterised by an analogous set of morphological features1 that depend on a proteolytic multigenic family, the caspases2,3. Each apoptotic signalling pathway involves a specific initiator caspase, upstream of the pathway regulation, which finally converges to common executioner caspases. Intrinsic apoptosis, previously known as the mitochondrial apoptotic pathway, is often considered as ancestral and evolutionary conserved among animals2,4–8. First identified in the nematode Caenorhabditis elegans, intrinsic apoptosis was next characterised in fruit fly Drosophila melanogaster and mammals. Intrinsic apoptosis depends on the key initiator caspase-9 (named Ced-3 and Dronc in Caenorhabditis and Drosophila, respectively), the activator Apaf-1 and the Bcl-2 multigenic family2,6,9. Many functional studies have led to a deep characterisation of intrinsic apoptosis based on those classical models. Nevertheless, the biochemical role of mitochondria, the pivotal function of cytochrome c and the modality of caspases activation remain highly heterogeneous and hide profound molecular divergences among apoptotic pathways in animals8,10. Independent of functional approaches, the phylogenetic history of the signal transduction actors, mostly the caspase family, is the Rosetta Stone to shed light on intrinsic apoptosis evolution. Here, after exhaustive research on CARD-caspases, we demonstrate by phylogenetic analysis that the caspase-9, the fundamental key of intrinsic apoptosis, is deuterostomes-specific, while it is the caspase-2 which is ancestral and common to bilaterians. Our analysis of Bcl-2 family and Apaf-1 confirm the high heterogeneity in apoptotic pathways elaboration in animals. Taken together, our results support convergent emergence of distinct intrinsic apoptotic pathways during metazoan evolution.