Precambrian origins of the TNFR superfamily

The evolution of the tumor necrosis factor/tumor necrosis factor receptor superfamily (TNF/TNFR) is complicated and not well understood. To date, most TNFR studies have focused on vertebrate models leaving the role of TNFRs in invertebrates largely unexplored. The evolution of important cellular processes including stress response, apoptosis, development, and inflammation will be better understood by examining the TNF/TNFR superfamily in ancient invertebrate phyla. How widespread is this gene family within the evolutionary tree of life and is there evidence for similar function in invertebrates? A first step is to identify the presence or absence of these genes within basal metazoan taxa using the signature cysteine-rich domain (CRD) of the TNFR superfamily. In this perspective, we will start by examining what is currently known about the function of TNFRs in invertebrates. Then, we will assess the role of TNFRs in apoptosis and explore the origins of the domains found in TNFRs including the death domain (DD) and CRD. Finally, we will examine the phylogenetic relationship between TNFRs containing DDs identified to date. From these data, we propose a model for a Precambrian origin of TNFRs and their functional role in apoptosis.