The highly conserved, nuclear-localized Akirin1 and Akirin2 proteins critically regulate the transcription of NF-κB-dependent genes and are required for defense against Gram-negative bacteria in the immune deficiency and NF-κB pathways. Akirin1 is dispensable in the mouse, and neither knockout mice nor cells derived from them have obvious distinctive phenotypes. In contrast, Akirin2 is required for development in the mouse and knockout of both Akirin homologs in mice show that Akirin2 is required downstream of toll-like receptor (TLR), TNF-α and IL-1β signaling, and for the production of IL-6. Akirin2 is functionally closer to the single gene in Drosophila, as the homozygous null D. melanogaster Akirin mutants show a similar, mid-to-early embryonic death.