Lys63-linked polyubiquitin chains: Linking more than just ubiquitin

Abstract

Polyubiquitin chains linked through the Lys48 residue of ubiquitin are most commonly associated with targeting proteins for proteosomal degradation. In contrast, polyubiquitin chains linked through the Lys63 residue of ubiquitin are associated with nonproteolytic functions such as signal transduction. The mechanism by which Lys63-linked polyubiquitin chains participate in signaling cascades has yet to be determined, but two recent publications (Wu et al., Nat Cell Bio 2006; 8:398-406 and Ea et al., Mol Cell 2006; 22:245-57) shed light on how this distinctive modification functions in NFκB activation by TNFα. Upon stimulation with TNFα, RIP1 undergoes Lys63-linked polyubiquitination. The polyubiquitin chain on RIP1 is recognized and bound by NEMO, the regulatory subunit of the IKK complex, and this binding is essential for NFκB activation by TNFα. Thus, Lys63-linked polyubiquitin chains critically connect components of NFκB signaling in a highly regulated manner. ©2006 Landes Bioscience.