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IL-1R-associated kinases (IRAK) are important regulators in the TLR/IL-1R pathways, but their function appears inconsistent between Drosophila, bony fishes, and vertebrates. This causes a difficulty to understand the IRAK functions. As a step to reveal the evolution of IRAKs, in this study, we performed comparative and functional analysis of IRAKs by exploiting the amphioxus, a pivotal taxon connecting invertebrates and vertebrates. Sequence and phylogenetic analysis indicated three major IRAK lineages: IRAK1/2/3 is a vertebrate-specific lineage, IRAK4 is an ancient lineage conserved between invertebrate and vertebrates, and Pelle is another ancient lineage that is preserved in protostomes and invertebrate deuterostomes but lost in vertebrate deuterostomes. Pelle is closer neither to IRAK4 nor to IRAK1/2/3, hence suggesting no clear functional analogs to IRAK1/2/3 in nonvertebrates. Functional analysis showed that both amphioxus IRAK4 and Pelle could suppress NF-kB activation induced by MyD88 and TRAF6, which are unlike mammalian and Drosophila IRAKs, but, surprisingly, similar to bony fish IRAK4. Also unlike Drosophila IRAKs, no interaction was detected between amphioxus IRAK4 and Pelle, although both of them were shown capable of binding MyD88. These findings, together with previous reports, show that unlike other signal transducers in the TLR/IL-1R pathways, such as MyD88 and TRAF6, the functions of IRAKs are highly variable during evolution and very specialized in different major animal taxa. Indeed, we suggest that the functional variability of IRAKs might confer plasticity to the signal transduction of the TLR/IL-1R pathways, which in return helps the species to evolve against the pathogens. [ABSTRACT FROM AUTHOR]