IL-17 receptor signaling: ubiquitin gets in on the act

Engagement of the interleukin-17 (IL-17) receptor complex triggers activation of the transcription factor nuclear factor kappaB (NF-kappaB). A wide array of signaling molecules can contribute to the activation of NF-kappaB, but a number of common themes link the receptors engaged to activate it with the translocation of the active complex to the nucleus; among these is a clear role for ubiquitination. Ubiquitination is essential to the degradation of the inhibitor of NF-kappaB (IkappaB) subunits, which otherwise retain the inactive NF-kappaB complex in the cytosol. However, additional roles for ubiquitination in the assembly of signaling complexes and in enzyme activation are underappreciated aspects of NF-kappaB induction pathways. These roles require a form of ubiquitination biochemically distinct from that which targets proteins for degradation. The identification of Act1, an adaptor protein of the IL-17 receptor, as an E3 ubiquitin ligase capable of initiating this modification provides an impressive connection between the IL-17 receptor complex and pathways that activate NF-kappaB.