| Summary: | Complement C3 plays a pivotal role in the innate immune system of mammals as the central component of the complement system essential for its activation mechanism and effecter function. C3 has a unique intra-chain thioester bond that is shared by some complement and non-complement proteins forming a thioester protein (TEP) family. Phylogenetic analysis of TEP family genes of vertebrates and invertebrates revealed that the TEP family is divided into two subfamilies, the C3 subfamily and the alpha-2-macroglobulin (A2M) subfamily. The establishment of the TEP genes and differentiation of them into the C3 and A2M subfamilies occurred prior to the divergence of Cnidaria and Bilateria, in a common ancestor of Eumetazoa more than 600 MYA. Since then the A2M subfamily has been retained by all metazoan lineages analyzed thus far. In contrast, the C3 subfamily has been retained only by deuterostomes and some protostomes, and has been lost in multiple protostome lineages. Although the direct functional analysis of the most invertebrate TEPs is still to be performed, conservation of the basic domain structure and functionally important residues for each molecule suggests that the basic function is also conserved. Functional analyses performed on a few invertebrate C3 support this conclusion. The gene duplication events that generated C4 and C5 from C3 occurred in a common ancestor of jawed vertebrates, indicating that invertebrate and cyclostome C3s represent the pre-duplication state. In addition to C3, complement Bf and MASP involved in the activation of C3 are also identified in Cnidaria and some invertebrates, indicating that the complement system is one of the most ancient innate immune systems of Eumetazoa.
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