Evolution of Apoptotic Signaling Pathways Within Lophotrochozoans

Abstract Apoptosis is the main form of regulated cell death in metazoans. Apoptotic pathways are well characterized in nematodes, flies, and mammals, leading to a vision of the conservation of apoptotic pathways in metazoans. However, we recently showed that intrinsic apoptosis is in fact divergent among metazoans. In addition, extrinsic apoptosis is poorly studied in non-mammalian animals, making its evolution unclear. Consequently, our understanding of apoptotic signaling pathways evolution is a black box which must be illuminated by extending research to new biological systems. Lophotrochozoans are a major clade of metazoans which, despite their considerable biological diversity and key phylogenetic position as sister group of ecdysozoans (i.e. flies and nematodes), are poorly explored, especially regarding apoptosis mechanisms. Traditionally, each apoptotic signaling pathway was considered to rely on a specific initiator caspase, associated with an activator. To shed light on apoptosis evolution in animals, we explored the evolutionary history of initiator caspases, caspase activators, and the BCL-2 family (which control mitochondrial apoptotic pathway) in lophotrochozoans using phylogenetic analysis and protein interaction predictions. We discovered a diversification of initiator caspases in molluscs, annelids, and brachiopods, and the loss of key extrinsic apoptosis components in platyhelminths, along with the emergence of a clade-specific caspase with an ankyrin pro-domain. Taken together, our data show a specific history of apoptotic actors’ evolution in lophotrochozoans, further demonstrating the appearance of distinct apoptotic signaling pathways during metazoan evolution.